NDUFS1

Chr 2AR

NADH:ubiquinone oxidoreductase core subunit S1

Also known as: CI-75Kd, CI-75k, MC1DN5, PRO1304

NCBI Gene: 4719 ENSG00000023228 UniProt: P28331 OMIM: 157655

The NDUFS1 protein is the largest subunit of mitochondrial complex I and functions as an NADH dehydrogenase that transfers electrons from NADH to ubiquinone in the respiratory chain, forming part of the active site where NADH is oxidized. Mutations cause mitochondrial complex I deficiency, nuclear type 5, which follows an autosomal recessive inheritance pattern. The pathogenic mechanism involves impaired electron transport chain function due to defective complex I assembly or activity.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene belongs to the complex I 75 kDa subunit family. Mammalian complex I is composed of 45 different subunits. It locates at the mitochondrial inner membrane. This protein has NADH dehydrogenase activity and oxidoreductase activity. It transfers electrons from NADH to the respiratory chain. The immediate electron acceptor for the enzyme is believed to be ubiquinone. This protein is the largest subunit of complex I and it is a component of the iron-sulfur (IP) fragment of the enzyme. It may form part of the active site crevice where NADH is oxidized. Mutations in this gene are associated with complex I deficiency. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2011]

OMIM ResearchGenerating clinical summary…

MultiplemechanismARLOEUF 0.811 OMIM phenotype

Clinical Summary— NDUFS1

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Gene-Disease Validity (ClinGen)

mitochondrial disease · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

51 unique Pathogenic / Likely Pathogenic· 206 VUS of 516 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.81LOEUF

pLI 0.000

Z-score 2.53

OE 0.57 (0.41–0.81)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

-0.08Z-score

OE missense 1.01 (0.93–1.10)

413 obs / 408.7 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.57 (0.41–0.81)

0≤0.351.4

Missense OE?1.01 (0.93–1.10)

0≤0.61.4

Synonymous OE?1.04

0≤1.21.6

LoF obs/exp: 23 / 40.3Missense obs/exp: 413 / 408.7Syn Z: -0.41

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveNDUFS1-related mitochondrial complex I deficiencyOTHERAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.6260th %ile

GOF

0.5170th %ile

LOF

0.4037th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

516 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic15

Likely Pathogenic36

VUS206

Likely Benign141

Benign67

Conflicting32

Pathogenic

Likely Pathogenic

206

VUS

141

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	12	3	0	0	15
Likely Pathogenic	16	19	1	0	36
VUS	0	174	28	4	206
Likely Benign	0	0	95	46	141
Benign	0	0	65	2	67
Conflicting	—				32
Total	28	196	189	52	497

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

26 pathogenic / likely-pathogenic (of 31) ClinVar copy-number / structural variants overlap NDUFS1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →