Curated summary · agent-written · kb/genes/curated/hgnc_7708.md

All 14 claims checked against the KB draft

NDUFS2 across dismech

NDUFS2 (NADH:ubiquinone oxidoreductase core subunit S2) is named by 1 disorder entry.

Normal function

ai-gene-review gives NDUFS2's core molecular function as ubiquinone binding, acting in mitochondrial electron transport, NADH to ubiquinone. The upstream review describes NDUFS2 as a catalytic core subunit of the complex I Q module that lines the ubiquinone-binding site; the terminal cluster N2 sits at its interface with NDUFS7 but is ligated by NDUFS7.

Disease record

The one entry naming NDUFS2, Mitochondrial Complex I Deficiency, Nuclear Type 6, types it as causative and records the variants as germline. The gene sits on the node NDUFS2 Loss of Function, and nodes naming it conform to the module complex_i_deficiency.

No process term on the KB's NDUFS2 nodes matches an ai-gene-review core process by exact identifier (0 shared); the entry records the gene's normal function as molecular-function and assembly terms on the nodes downstream of the gene node instead.

ClinGen

ClinGen classifies NDUFS2 for 2 diseases. The one with no dismech entry is mitochondrial disease, and the dismech entries matched to a ClinGen disease for NDUFS2 that do not type the gene are Leber-like Hereditary Optic Neuropathy, Autosomal Recessive 1; and Leigh Syndrome.

Underlined values are claims re-computed from the knowledge base each time this page is built. The tables below are the source of truth.

Normal function · from ai-gene-review (O75306, commit 79fe13b38970) · AI-generated, not KB evidence

NDUFS2 encodes the 49 kDa subunit of mitochondrial Complex I (NADH:ubiquinone oxidoreductase, EC 7.1.1.2), and is a core catalytic subunit of the Q-module in the peripheral (matrix-facing) arm. NDUFS2 directly contributes to the ubiquinone-binding channel, providing the conserved His59/Tyr108 residue pair that contacts and orients the ubiquinone headgroup during reduction. A [4Fe-4S] cluster has been assigned to NDUFS2 by similarity to the NiFe-hydrogenase large subunit fold it retains, but no structure of mammalian Complex I places a cluster on this subunit; the terminal N2 cluster that delivers electrons to the quinone site is ligated by NDUFS7. NDUFS2 is essential for both Complex I assembly and catalytic activity. NDUFS2 is dimethylated at Arg-85 (Arg-118 in precursor numbering) by the assembly factor NDUFAF7, a modification required for stabilization of early assembly intermediates. NDUFS2 is also a redox-sensitive component implicated in acute oxygen sensing in pulmonary artery smooth muscle cells, where its cysteine residues become reduced under hypoxia, inhibiting Complex I and triggering hypoxic pulmonary vasoconstriction. Pathogenic mutations cause mitochondrial Complex I deficiency (MC1DN6, presenting as Leigh syndrome) and Leber-like hereditary optic neuropathy (LHONAR2).

NDUFS2 is the 49 kDa core catalytic subunit of mitochondrial Complex I (NADH:ubiquinone oxidoreductase, EC 7.1.1.2), located in the Q-module of the peripheral (matrix-facing) arm. It directly forms the ubiquinone-binding channel with the conserved His59/Tyr108 residue pair that contacts and orients the ubiquinone headgroup during reduction. UniProt annotates one [4Fe-4S] cluster on NDUFS2 by similarity (ECO:0000255); this is not the N2 cluster, which is ligated by NDUFS7/PSST. NDUFS2 enables ubiquinone binding (GO:0048039) at the terminus of the Fe-S relay chain, and contributes to the overall NADH dehydrogenase (ubiquinone) activity (GO:0008137) of the 45-subunit Complex I holoenzyme. The Asp446Asn mutation near the coenzyme Q binding pocket specifically impairs catalytic activity without affecting complex assembly, demonstrating NDUFS2's direct role in the enzymatic reaction. NDUFS2 is dimethylated at Arg-85 by the assembly factor NDUFAF7, a modification required for stabilization of early assembly intermediates. Pathogenic mutations cause mitochondrial Complex I deficiency (MC1DN6, Leigh syndrome) and Leber-like hereditary optic neuropathy (LHONAR2).

molecular function: ubiquinone binding · contributes to molecular function: NADH dehydrogenase (ubiquinone) activity · directly involved in: mitochondrial electron transport, NADH to ubiquinone · locations: mitochondrial inner membrane; mitochondrial matrix · in complex: respiratory chain complex I

In the knowledge base · computed from kb/ at build time

Disorders

Relationship is the entry's genetic[].relationship_type. untyped means the entry has a genetic record for the gene but does not type it; its free-text association is shown instead.

Disorder	Relationship	Where the gene appears
Mitochondrial Complex I Deficiency, Nuclear Type 6	causative germline loss of function	mechanism: Loss of the N2 Iron-Sulfur Cluster and Quinone Reduction; NDUFS2 Loss of Function

ClinGen gene–disease validity · snapshot 2026-10-03 · matched to entries by MONDO

An entry matches when ClinGen's MONDO disease is the entry's own disease term, a subtype term, or an exact-match mapping. An amber status marks an entry ClinGen supports the gene for (Definitive, Strong or Moderate) whose own record does not type it. A Limited, Disputed or Refuted tier on such an entry is not a gap.

ClinGen disease	MOI	Classification	dismech entry
Leigh syndrome MONDO:0009723	AR	Definitive 2021-04-09	Leber-like Hereditary Optic Neuropathy, Autosomal Recessive 1 not named Leigh Syndrome not named
mitochondrial disease MONDO:0044970	AR	Definitive 2024-01-18	no dismech entry

Mechanism modules · computed from kb/

complex_i_deficiency via Mitochondrial Complex I Deficiency, Nuclear Type 6