RAB5C-Related Neurodevelopmental Disorder with Macrocephaly

Mendelian Pathograph 4 Show in embeddings browser Neurodevelopmental Disorder Developmental Delay RAB protein disorder

RAB5C-related neurodevelopmental disorder with macrocephaly is a rare autosomal dominant developmental disorder caused by de novo RAB5C variants. RAB5C encodes an early endocytic Rab GTPase involved in endocytosis, membrane-protein recycling, and signaling. Reported missense variants alter nucleotide exchange and effector interactions, disrupt endocytic-pathway function in model systems, and produce a neurodevelopmental syndrome characterized mainly by macrocephaly and mild-to-moderate developmental delay; loss-of-function variants have been associated with a more severe seizure and intellectual-disability presentation.

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1
Inheritance
3
Pathophys.
4
Phenotypes
4
Pathograph
1
Genes
1
Deep Research
🏷

Classifications

👪

Inheritance

1
Autosomal dominant inheritance HP:0000006
The main published cohort reported heterozygous de novo RAB5C variants in affected individuals.
Autosomal dominant inheritance
Show evidence (1 reference)
PMID:37552066 SUPPORT Human Clinical
"Here we report on 12 individuals with nine different heterozygous de novo variants in RAB5C."
Heterozygous de novo variants support autosomal dominant RAB5C-related disease.
⚙

Pathophysiology

3
RAB5C GTPase regulatory defect
Pathogenic RAB5C variants perturb the Rab GTPase switch that regulates early endosomal trafficking, membrane-protein recycling, and signaling.
RAB5C hgnc:9785
endocytosis GO:0006897 ⚠ ABNORMAL receptor-mediated endocytosis GO:0006898 ⚠ ABNORMAL vesicle-mediated transport GO:0016192 ⚠ ABNORMAL
Downstream
Endocytic-pathway dysfunction Altered RAB5C GTPase behavior disrupts endocytic pathway function in vivo.
Show evidence (2 references)
PMID:37552066 SUPPORT Other
"RAB5C is a member of the Rab GTPase family that plays an important role in the endocytic pathway, membrane protein recycling and signaling."
The disease report defines the relevant RAB5C pathway context.
PMID:37552066 SUPPORT In Vitro
"In vitro biochemical studies revealed that all four variants were damaging, resulting in increased nucleotide exchange rate, attenuated responsivity to guanine exchange factors and heterogeneous effects on interactions with effector proteins."
Biochemical assays support altered RAB5C GTPase regulation and effector interaction as the primary molecular defect.
Endocytic-pathway dysfunction
Disrupted RAB5C-dependent endocytosis and recycling perturb developmental signaling and cellular trafficking during brain and organismal development.
endosome organization GO:0007032 ⚠ ABNORMAL intracellular protein transport GO:0006886 ⚠ ABNORMAL
Downstream
Neurodevelopmental macrocephaly phenotype Endocytic pathway disruption is associated with macrocephaly and developmental delay in affected individuals.
Show evidence (1 reference)
PMID:37552066 SUPPORT Model Organism
"Expression of the human RAB5C variants in zebrafish embryos resulted in defective development"
Zebrafish expression data support developmental consequences of the human RAB5C variants.
Neurodevelopmental macrocephaly phenotype
RAB5C-associated endocytic dysfunction manifests primarily as macrocephaly with developmental delay, with more severe epileptic encephalopathy reported in a smaller loss-of-function subset.
neuron CL:0000540
Show evidence (1 reference)
PMID:37552066 SUPPORT Human Clinical
"Our combined bioinformatic, in vitro and in vivo experimental studies and clinical data support the association of RAB5C missense variants with a neurodevelopmental disorder characterized by macrocephaly and mild-to-moderate developmental delay through disruption of the endocytic pathway."
The published cohort defines the core phenotype and mechanism.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for RAB5C-Related Neurodevelopmental Disorder with Macrocephaly Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

4
Head and Neck 1
Macrocephaly Macrocephaly HP:0000256
Show evidence (1 reference)
PMID:37552066 SUPPORT Human Clinical
"neurodevelopmental disorder characterized by macrocephaly"
The abstract states macrocephaly as a defining feature.
Nervous System 3
Global developmental delay Global developmental delay HP:0001263
Show evidence (1 reference)
PMID:37552066 SUPPORT Human Clinical
"macrocephaly and mild-to-moderate developmental delay"
The abstract defines developmental delay as part of the core syndrome.
Intellectual disability Intellectual disability HP:0001249
Show evidence (1 reference)
PMID:37552066 SUPPORT Human Clinical
"refractory epilepsy and intellectual disability"
The report describes intellectual disability in the more severe loss-of-function subset.
Seizures Seizure HP:0001250
Show evidence (1 reference)
PMID:37552066 SUPPORT Human Clinical
"refractory epilepsy and intellectual disability"
The abstract reports refractory epilepsy in patients with loss-of-function variants.
🧬

Genetic Associations

1
RAB5C heterozygous de novo pathogenic variants (Genetic variation)
Gene: RAB5C hgnc:9785 relationship_type: CAUSATIVE
Autosomal dominant inheritance
Show evidence (1 reference)
PMID:37552066 SUPPORT Human Clinical
"Here we report on 12 individuals with nine different heterozygous de novo variants in RAB5C."
The cohort establishes the variant class and de novo occurrence.
{ }

Source YAML

click to show 
name: RAB5C-Related Neurodevelopmental Disorder with Macrocephaly
creation_date: "2026-07-06T12:00:00Z"
category: Mendelian
description: >-
  RAB5C-related neurodevelopmental disorder with macrocephaly is a rare
  autosomal dominant developmental disorder caused by de novo RAB5C variants.
  RAB5C encodes an early endocytic Rab GTPase involved in endocytosis,
  membrane-protein recycling, and signaling. Reported missense variants alter
  nucleotide exchange and effector interactions, disrupt endocytic-pathway
  function in model systems, and produce a neurodevelopmental syndrome
  characterized mainly by macrocephaly and mild-to-moderate developmental delay;
  loss-of-function variants have been associated with a more severe seizure and
  intellectual-disability presentation.
parents:
- Neurodevelopmental Disorder
- Developmental Delay
- RAB protein disorder
synonyms:
- RAB5C-related macrocephaly and developmental delay
- RAB5C-related RAS-associated protein deficiency
- RAB5C deficiency
notes: >-
  WP-068 seed OMIM:604037 appears to identify RAB5C/RAB5C-related OMIM content
  rather than a clearly separated disease class in the local MONDO release. No
  exact MONDO disease term was found locally, so disease_term is intentionally
  omitted pending ontology coverage. The curated name follows the 2023 disease
  report title and phenotype rather than the package seed phrase alone.
external_assertions:
- name: OMIM RAB5C seed identifier
  source: OMIM
  assertion_type: seed_identifier
  external_id: OMIM:604037
  description: >-
    OMIM identifier supplied by WP-068 for the RAB5C-related seed; curated here
    as a provisional external assertion pending exact disease ontology mapping.
classifications:
  icimd_category:
  - classification_value: vesicular_trafficking
    notes: >-
      WP-068 classification 19.6.69.01: Complex Molecule and Organelle
      Metabolism, disorders of organelle biogenesis, dynamics and interactions,
      disorders of vesicular trafficking.
inheritance:
- name: Autosomal dominant inheritance
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    The main published cohort reported heterozygous de novo RAB5C variants in
    affected individuals.
  evidence:
  - reference: PMID:37552066
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we report on 12 individuals with nine different heterozygous de novo
      variants in RAB5C.
    explanation: >-
      Heterozygous de novo variants support autosomal dominant RAB5C-related
      disease.
pathophysiology:
- name: RAB5C GTPase regulatory defect
  description: >-
    Pathogenic RAB5C variants perturb the Rab GTPase switch that regulates early
    endosomal trafficking, membrane-protein recycling, and signaling.
  genes:
  - preferred_term: RAB5C
    term:
      id: hgnc:9785
      label: RAB5C
  biological_processes:
  - preferred_term: endocytosis
    modifier: ABNORMAL
    term:
      id: GO:0006897
      label: endocytosis
  - preferred_term: receptor-mediated endocytosis
    modifier: ABNORMAL
    term:
      id: GO:0006898
      label: receptor-mediated endocytosis
  - preferred_term: vesicle-mediated transport
    modifier: ABNORMAL
    term:
      id: GO:0016192
      label: vesicle-mediated transport
  evidence:
  - reference: PMID:37552066
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      RAB5C is a member of the Rab GTPase family that plays an important role in
      the endocytic pathway, membrane protein recycling and signaling.
    explanation: >-
      The disease report defines the relevant RAB5C pathway context.
  - reference: PMID:37552066
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In vitro biochemical studies revealed that all four variants were damaging,
      resulting in increased nucleotide exchange rate, attenuated responsivity to
      guanine exchange factors and heterogeneous effects on interactions with
      effector proteins.
    explanation: >-
      Biochemical assays support altered RAB5C GTPase regulation and effector
      interaction as the primary molecular defect.
  downstream:
  - target: Endocytic-pathway dysfunction
    causal_link_type: DIRECT
    description: >-
      Altered RAB5C GTPase behavior disrupts endocytic pathway function in vivo.
    evidence:
    - reference: PMID:37552066
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Studies in C. elegans confirmed that all four variants were damaging in
        vivo and showed defects in endocytic pathway function.
      explanation: >-
        C. elegans experiments directly support endocytic-pathway dysfunction.
- name: Endocytic-pathway dysfunction
  description: >-
    Disrupted RAB5C-dependent endocytosis and recycling perturb developmental
    signaling and cellular trafficking during brain and organismal development.
  biological_processes:
  - preferred_term: endosome organization
    modifier: ABNORMAL
    term:
      id: GO:0007032
      label: endosome organization
  - preferred_term: intracellular protein transport
    modifier: ABNORMAL
    term:
      id: GO:0006886
      label: intracellular protein transport
  evidence:
  - reference: PMID:37552066
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Expression of the human RAB5C variants in zebrafish embryos resulted in
      defective development
    explanation: >-
      Zebrafish expression data support developmental consequences of the human
      RAB5C variants.
  downstream:
  - target: Neurodevelopmental macrocephaly phenotype
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Endocytic pathway disruption is associated with macrocephaly and
      developmental delay in affected individuals.
    evidence:
    - reference: PMID:37552066
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        a neurodevelopmental disorder characterized by macrocephaly and
        mild-to-moderate developmental delay through disruption of the endocytic
        pathway.
      explanation: >-
        The report explicitly connects endocytic pathway disruption to the
        macrocephaly/developmental-delay syndrome.
- name: Neurodevelopmental macrocephaly phenotype
  description: >-
    RAB5C-associated endocytic dysfunction manifests primarily as macrocephaly
    with developmental delay, with more severe epileptic encephalopathy reported
    in a smaller loss-of-function subset.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  evidence:
  - reference: PMID:37552066
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our combined bioinformatic, in vitro and in vivo experimental studies and
      clinical data support the association of RAB5C missense variants with a
      neurodevelopmental disorder characterized by macrocephaly and
      mild-to-moderate developmental delay through disruption of the endocytic
      pathway.
    explanation: >-
      The published cohort defines the core phenotype and mechanism.
phenotypes:
- category: Growth
  name: Macrocephaly
  phenotype_term:
    preferred_term: Macrocephaly
    term:
      id: HP:0000256
      label: Macrocephaly
  description: >-
    Macrocephaly is the defining head-size phenotype in the missense-variant
    cohort.
  evidence:
  - reference: PMID:37552066
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "neurodevelopmental disorder characterized by macrocephaly"
    explanation: >-
      The abstract states macrocephaly as a defining feature.
- category: Neurological
  name: Global developmental delay
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  description: >-
    Mild-to-moderate developmental delay is part of the core presentation.
  evidence:
  - reference: PMID:37552066
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "macrocephaly and mild-to-moderate developmental delay"
    explanation: >-
      The abstract defines developmental delay as part of the core syndrome.
- category: Neurological
  name: Intellectual disability
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  description: >-
    Intellectual disability is reported especially in the more severe
    loss-of-function presentations.
  evidence:
  - reference: PMID:37552066
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "refractory epilepsy and intellectual disability"
    explanation: >-
      The report describes intellectual disability in the more severe
      loss-of-function subset.
- category: Neurological
  name: Seizures
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  description: >-
    Refractory epilepsy has been reported in the smaller loss-of-function
    subset.
  evidence:
  - reference: PMID:37552066
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "refractory epilepsy and intellectual disability"
    explanation: >-
      The abstract reports refractory epilepsy in patients with loss-of-function
      variants.
genetic:
- name: RAB5C heterozygous de novo pathogenic variants
  association: Genetic variation
  relationship_type: CAUSATIVE
  presence: Pathogenic
  gene_term:
    preferred_term: RAB5C
    term:
      id: hgnc:9785
      label: RAB5C
  inheritance:
  - name: Autosomal dominant inheritance
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  features: >-
    Most reported pathogenic variants are heterozygous de novo missense alleles
    with damaging biochemical and model-organism effects; a smaller number of
    loss-of-function alleles were associated with more severe neurologic disease.
  evidence:
  - reference: PMID:37552066
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we report on 12 individuals with nine different heterozygous de novo
      variants in RAB5C.
    explanation: >-
      The cohort establishes the variant class and de novo occurrence.
📚

References & Deep Research

Deep Research

1
RAB5C-Related Neurodevelopmental Disorder with Macrocephaly Deep Research Fallback ▸

RAB5C-Related Neurodevelopmental Disorder with Macrocephaly Deep Research Fallback

Scope

No provider-generated deep research artifact was present on the WP-068 branch. This fallback audit documents the literature scope used to curate and review the RAB5C-related entry from cached PubMed references.

Evidence Scope Used For Curation

  • PMID:37552066 for the RAB5C cohort, heterozygous de novo variant evidence, RAB5C endocytic-pathway biology, damaging biochemical effects on nucleotide exchange and effector interactions, C. elegans and zebrafish functional evidence, and the clinical phenotype of macrocephaly with mild-to-moderate developmental delay plus a smaller severe seizure/intellectual-disability subset.

Curation Conclusions

The supported model is heterozygous pathogenic RAB5C variation disrupting the early endocytic Rab GTPase cycle and downstream endocytic pathway function. The current evidence supports a provisional gene-defined neurodevelopmental entry with macrocephaly, developmental delay, intellectual disability, and seizures; no exact local MONDO disease class was identified on this branch.