| Variant / protein change | cDNA change | Variant type | Source / case context | Protein region / domain affected | Clustering pattern | Reported / inferred functional consequence | Pathogenicity classification / evidence level | CADD / in silico data | Conservation / population data | Key notes / citations |
|---|---|---|---|---|---|---|---|---|---|---|
| p.Pro42Leufs*6 | c.125del | Frameshift | Blok 2018 patient A | N-terminus, upstream of annotated Med13_N domain | Non-clustered truncating variant | Predicted premature termination; likely loss of normal function | Likely pathogenic / pathogenic by case-series evidence | CADD 31.0 | Absent from gnomAD/TOPMed in cohort analysis | Associated with mild ID and speech apraxia in original cohort (pqac-00000001, pqac-00000006, pqac-00000015) |
| p.Leu131* | c.392T>G | Nonsense | Blok 2018 patients B/C | N-terminal region, upstream of Med13_N domain | Recurrent truncating variant | Predicted truncation; transcript detected on cDNA, but no truncated protein detected in analogous nonsense case, supporting abnormal protein consequence rather than simple transcript loss | Pathogenic by segregation/case evidence | CADD 37.0 | Absent from gnomAD/TOPMed in cohort analysis | One inherited instance from affected mother to affected child shows AD transmission with variable expressivity (pqac-00000001, pqac-00000006, pqac-00000015) |
| p.Thr326Ile | c.977C>T | Missense | Blok 2018 patient D | Conserved N-terminal phosphodegron within/near Med13_N domain | N-terminal hotspot | Predicted to impair FBW7 phosphodegron recognition and alter MED13 ubiquitination/degradation, potentially increasing abnormal MED13 stability | Likely pathogenic by clustering/mechanistic evidence | CADD 25.0 | Site highly conserved; codon under strong selection; absent from gnomAD/TOPMed | One of four variants affecting Thr326/Pro327 hotspot (pqac-00000008, pqac-00000015) |
| p.Thr326del | c.975_977delTAC | In-frame deletion | Blok 2018 patient E | Conserved N-terminal phosphodegron within/near Med13_N domain | N-terminal hotspot | Predicted disruption of phosphodegron and impaired SCF-FBW7-mediated degradation | Likely pathogenic by hotspot/mechanistic evidence | CADD 20.5 | Highly conserved motif; absent from gnomAD/TOPMed | Only in-frame deletion in original cohort; still localized to same hotspot as missense variants (pqac-00000008, pqac-00000015) |
| p.Pro327Ser | c.979C>T | Missense | Blok 2018 patient F; Nardi 2021; recurrent in later reports | Conserved N-terminal phosphodegron within/near Med13_N domain | N-terminal hotspot, recurrent | Predicted to reduce phosphodegron-dependent FBW7 binding and MED13 turnover | Likely pathogenic; recurrent across unrelated patients | CADD 23.4 | Highly conserved residue; absent from gnomAD/TOPMed | Recurrent variant with variable expressivity, from neurodevelopmental phenotype to Kabuki-like presentation (pqac-00000005, pqac-00000006, pqac-00000008, pqac-00000015) |
| p.Pro327Gln | c.980C>A | Missense | Blok 2018 patient G | Conserved N-terminal phosphodegron within/near Med13_N domain | N-terminal hotspot | Same predicted mechanism as other phosphodegron variants: altered phosphorylation/FBW7 interaction and defective degradation | Likely pathogenic by hotspot/mechanistic evidence | CADD 25.2 | Highly conserved; absent from gnomAD/TOPMed | Supports hotspot-specific mechanism at adjacent residues Thr326/Pro327 (pqac-00000008, pqac-00000015) |
| p.Pro540Thr | c.1618C>A | Missense | Blok 2018 patient H | Internal conserved linear motif outside named Pfam domains | Non-hotspot missense | Predicted formation of novel Casein Kinase 1 phosphorylation motif and altered protein interactions | VUS-to-likely pathogenic range by case/mechanistic evidence | CADD 26.3 | Highly conserved motif; codon under strong selection; absent from gnomAD/TOPMed | Distinct mechanism proposed versus phosphodegron variants (pqac-00000008, pqac-00000015) |
| p.Leu582* | c.1745T>A | Nonsense | Blok 2018 patient I | Internal region between N- and C-terminal domains | Non-clustered truncating variant | Predicted loss of downstream functional regions and loss of normal function | Pathogenic by case evidence | CADD 40.0 | Absent from gnomAD/TOPMed | Truncating variants distributed outside missense hotspots (pqac-00000006, pqac-00000008) |
| p.Arg1400* | c.4198C>T | Nonsense | Blok 2018 patient J | Mid-protein region, upstream of Med13_C domain | Non-clustered truncating variant | cDNA present, but no truncated protein detected on western blot; supports abnormal protein consequence / defective stable product | Pathogenic by functional follow-up | CADD 41.0 | Absent from gnomAD/TOPMed | Functional transcript/protein analyses were performed for this allele (pqac-00000008, pqac-00000015) |
| p.Thr1496Metfs*11 | c.4487delC | Frameshift | Blok 2018 patient K | Mid/C-terminal transition, upstream of Med13_C domain | Non-clustered truncating variant | Predicted premature truncation with loss of C-terminal region | Pathogenic by case evidence | CADD 35.0 | Absent from gnomAD/TOPMed | Associated with severe speech disorder/regression in cohort (pqac-00000006, pqac-00000008) |
| p.Gln2060Lys | c.6178C>A | Missense | Blok 2018 patient L | C-terminal Med13_C domain | C-terminal hotspot | Predicted disturbance of conserved surface-exposed motif / interaction interface | Likely pathogenic by clustering and conservation | CADD 24.1 | Highly conserved; absent from gnomAD/TOPMed | One of two adjacent C-terminal hotspot variants in patients with eye findings including Duane anomaly (pqac-00000006, pqac-00000008, pqac-00000015) |
| p.Ala2064Val | c.6191C>T | Missense | Blok 2018 patient M | C-terminal Med13_C domain | C-terminal hotspot | Predicted structural alteration with increased hydrophobic collapse and reduced linear interaction potential on conserved surface motif | Likely pathogenic by structural modeling | CADD 25.7 | Highly conserved; absent from gnomAD/TOPMed | Supports second missense hotspot in C-terminal region (pqac-00000006, pqac-00000008, pqac-00000015) |
| p.Pro835Ser | reported as de novo missense variant in 2024 case report | Missense | Tolmacheva 2024 severe neonatal case | Mid-protein region, outside named hotspot in available summary | Non-hotspot missense | Not mapped to a known functional center in UniProt summary, but predicted damaging; may underlie severe multisystem/neonatal phenotype | Likely pathogenic per ACMG in report | CADD 26.1; PolyPhen-2 0.996; SIFT 0.0 | Position conserved across vertebrates per UCSC alignment; de novo; absent/rare in population databases implied by diagnostic filtering | Expanded phenotype to severe neonatal presentation and death (pqac-00000002, pqac-00000016) |
| p.Arg1882Serfs*9 | c.5641delinsTC | Frameshift | Yang 2025 Chinese family | Distal C-terminal half, upstream of Med13_C tail end | Non-clustered truncating variant | Predicted truncation with autosomal dominant disease mechanism | Pathogenic/likely pathogenic by familial segregation and ACMG-based interpretation | Not numerically reported in excerpt | Rare after filtering at MAF ≤0.001; segregated with affected mother and proband | First reported Chinese family; supports inherited AD disease and expands variant spectrum (pqac-00000004, pqac-00000017) |
| Overall MED13 variant spectrum | Multiple | Missense, nonsense, frameshift, in-frame deletion | Blok 2018 + recent reports | Two annotated Pfam domains: Med13_N (aa 11-383) and Med13_C (aa 1640-2163), plus conserved internal motifs | Strong clustering of non-truncating variants in two regions: N-terminal phosphodegron hotspot (Thr326/Pro327) and C-terminal hotspot around Gln2060/Ala2064 | Truncating variants support loss-of-function/haploinsufficiency-like mechanism; hotspot missense variants suggest altered degradation or altered protein interaction surfaces | Disease-gene relationship supported by significant enrichment of de novo variants in DD/ID cohorts (p=0.00371) | CADD range for reported 2018 variants: 20.5-41.0 | All 12 unique Blok 2018 variants absent from gnomAD and TOPMed; missense hotspot residues highly conserved and under codon selection | Best current model is mixed mechanism: truncating alleles causing loss of normal function and clustered missense alleles perturbing regulated MED13 turnover or conserved interaction motifs (pqac-00000008, pqac-00000015, pqac-00000017) |


*Table: This table summarizes the reported genetic and molecular features of MED13 syndrome, including representative variants, domains, clustering, functional interpretations, and available in silico evidence. It is useful for disease knowledge base curation and for distinguishing truncating versus hotspot missense mechanisms.*