NDUFS8

Chr 11AR

NADH:ubiquinone oxidoreductase core subunit S8

Also known as: CI-23k, CI23KD, MC1DN2, TYKY

The protein is a subunit of mitochondrial Complex I that binds iron-sulfur clusters and is required for electron transfer in the respiratory chain. Mutations cause mitochondrial complex I deficiency and Leigh syndrome through autosomal recessive inheritance. The pathogenic mechanism involves impaired NADH oxidation and disrupted mitochondrial energy production.

GeneReviewsOMIMResearchSummary from RefSeq, OMIM, UniProt
LOFmechanismARLOEUF 0.741 OMIM phenotype
Clinical SummaryNDUFS8
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Gene-Disease Validity (ClinGen)
Leigh syndrome · ARModerate

Moderate evidence — consider for supplementary testing

2 total gene-disease associations curated

Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.29) despite low pLI — interpret in context.
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ClinVar Variants
29 unique Pathogenic / Likely Pathogenic· 74 VUS of 183 total submissions
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GeneReview available — NDUFS8
Authoritative clinical overview · Recommended first read
Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

Tolerant — LoF & missense variants common in population
LoF Constraint
0.74LOEUF
pLI 0.166
Z-score 2.15
OE 0.29 (0.130.74)
Tolerant

Typical tolerance to LoF variation

Missense Constraint
0.74Z-score
OE missense 0.83 (0.710.96)
119 obs / 144.1 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.29 (0.130.74)
00.351.4
Missense OE0.83 (0.710.96)
00.61.4
Synonymous OE1.10
01.21.6
LoF obs/exp: 3 / 10.5Missense obs/exp: 119 / 144.1Syn Z: -0.59
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
definitiveNDUFS8-related mitochondrial respiratory chain complex I deficiencyLOFAR

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

DN
0.6358th %ile
GOF
0.6345th %ile
LOF
0.3939th %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.

ClinVar Variant Classifications

183 submitted variants in ClinVar

Classification Summary

Pathogenic11
Likely Pathogenic18
VUS74
Likely Benign48
Benign11
Conflicting16
11
Pathogenic
18
Likely Pathogenic
74
VUS
48
Likely Benign
11
Benign
16
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
4
7
0
11
Likely Pathogenic
4
9
5
0
18
VUS
2
64
8
0
74
Likely Benign
0
0
22
26
48
Benign
0
0
11
0
11
Conflicting
16
Total6775326178

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

View in ClinVar →

Protein Context — Lollipop Plot

NDUFS8 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Open Research Assistant →