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.

GeneReviews 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]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Mitochondrial complex I deficiency, nuclear type 5MIM #618226

Clinical highlights

Gene–disease validity (ClinGen · GenCC)

Definitive · mitochondrial disease · AR · ClinGen 2023
Definitive · Leigh syndrome · AR · ClinGen 2019
Definitive · mitochondrial complex I deficiency, nuclear type 5 · AR · G2P
Supportive · mitochondrial complex I deficiency · AR · Orphanet

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.81

LOEUF

Mechanism· predicted

📖

GeneReview available — NDUFS1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

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

Background carrier burden — how many people carry a rare variant somewhere in NDUFS1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 65

979 rare PASS variants

Rare truncating (LoF)

1 in 990

153 rare PASS variants

Rare synonymous (reference)

1 in 220

307 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for NDUFS1. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 76	1 in 1,100
South Asian	~43k	1 in 60	1 in 690
Remaining (unassigned)	~30k	1 in 47	1 in 900
European (Finnish)	~27k	1 in 360	1 in 3,300
Admixed American	~22k	1 in 56	1 in 1,600
African / African American	~21k	1 in 70	1 in 720
East Asian	~20k	1 in 59	1 in 300
Ashkenazi Jewish	~13k	1 in 200	1 in 960
Middle Eastern	~2,884	1 in 65	≈ 1 in 2,900

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 16 of 18 coding exons well covered in gnomAD exomes; exons 2, 4 marginal. Genomes: 17 of 18 (exon 4 below).? see exons ↓