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…

Primary Disease Associations & Inheritance

Mitochondrial complex I deficiency, nuclear type 33MIM #618253

Clinical highlights

Gene–disease validity (ClinGen)

Moderate · mitochondrial disease · AR · ClinGen 2024

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.71

LOEUF

LOF

Mechanism· G2P

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

Background carrier burden — how many people carry a rare variant somewhere in NDUFA6?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 280

253 rare PASS variants

Rare truncating (LoF)

1 in 1,500

48 rare PASS variants

Rare synonymous (reference)

1 in 280

102 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for NDUFA6. 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 250	1 in 1,400
South Asian	~43k	1 in 110	1 in 2,100
Remaining (unassigned)	~30k	1 in 160	1 in 1,900
European (Finnish)	~27k	1 in 3,300	1 in 3,800
Admixed American	~22k	1 in 140	1 in 1,000
African / African American	~21k	1 in 130	1 in 1,700
East Asian	~20k	1 in 250	1 in 2,500
Ashkenazi Jewish	~13k	1 in 820	none seen
Middle Eastern	~2,884	1 in 160	≈ 1 in 960

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): All 3 coding exons well covered in gnomAD exomes and genomes.? see exons ↓