NDUFA6

Chr 22AR

NADH:ubiquinone oxidoreductase subunit A6

Also known as: B14, CI-B14, LYRM6, MC1DN33, NADHB14

NCBI Gene: 4700 ENSG00000184983 UniProt: P56556 OMIM: 602138

The protein is an accessory subunit of mitochondrial Complex I (NADH dehydrogenase) that is required for proper enzyme assembly and functions in electron transfer from NADH to the respiratory chain. Mutations cause mitochondrial complex I deficiency, nuclear type 33, which follows autosomal recessive inheritance. The gene shows low constraint to loss-of-function variation (pLI 0.0001, LOEUF 1.714), suggesting haploinsufficiency is not the primary disease mechanism.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a member of the LYR family of proteins that contain a highly conserved tripeptide (LYR) motif near the N-terminus. The encoded protein is an accessory subunit of NADH: ubiquinone oxidorerductase (Complex I), which is the largest enzyme of the mitochondrial membrane respiratory chain. Complex I functions in electron transfer from NADH to the respiratory chain. [provided by RefSeq, Oct 2016]

OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 1.711 OMIM phenotype

Clinical Summary— NDUFA6

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Gene-Disease Validity (ClinGen)

mitochondrial disease · ARModerate

Moderate evidence — consider for supplementary testing

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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

7 unique Pathogenic / Likely Pathogenic· 41 VUS of 88 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?

1.71LOEUF

pLI 0.000

Z-score 0.17

OE 0.93 (0.50–1.71)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.80Z-score

OE missense 1.24 (1.06–1.45)

111 obs / 89.7 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.93 (0.50–1.71)

0≤0.351.4

Missense OE?1.24 (1.06–1.45)

0≤0.61.4

Synonymous OE?1.60

0≤1.21.6

LoF obs/exp: 6 / 6.5Missense obs/exp: 111 / 89.7Syn Z: -2.70

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongNDUFA6-related early onset isolated mitochondrial complex I deficiencyLOFAR

This gene — mechanism propensity

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

0.7327th %ile

GOF

0.6540th %ile

LOF

0.3454th %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

88 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic4

Likely Pathogenic3

VUS41

Likely Benign25

Benign3

Conflicting3

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	3	1	0	0	4
Likely Pathogenic	3	0	0	0	3
VUS	3	31	7	0	41
Likely Benign	0	2	10	13	25
Benign	0	1	2	0	3
Conflicting	—				3
Total	9	35	19	13	79

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

View in ClinVar →

27 pathogenic / likely-pathogenic (of 36) ClinVar copy-number / structural variants overlap NDUFA6 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →