TMEM126B

Chr 11AR

transmembrane protein 126B

Also known as: HT007, MC1DN29

NCBI Gene: 55863 ENSG00000171204 UniProt: Q8IUX1 OMIM: 615533

This mitochondrial transmembrane protein functions as an assembly factor required for formation of the membrane arm of complex I within the MCIA assembly complex. Mutations cause mitochondrial complex I deficiency with autosomal recessive inheritance. The gene shows low constraint to loss-of-function variation, consistent with the recessive disease pattern.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a mitochondrial transmembrane protein which is a component of the mitochondrial complex I assembly complex. The encoded protein serves as an assembly factor that is required for formation of the membrane arm of the complex. It interacts with NADH dehydrogenase [ubiquinone] 1 alpha subcomplex assembly factor 13. Naturally occurring mutations in this gene are associated with isolated complex I deficiency. A pseudogene of this gene has been defined on chromosome 9. [provided by RefSeq, Apr 2017]

OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 1.641 OMIM phenotype

Clinical Summary— TMEM126B

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Gene-Disease Validity (ClinGen)

mitochondrial disease · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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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

17 unique Pathogenic / Likely Pathogenic· 57 VUS of 135 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?

1.64LOEUF

pLI 0.000

Z-score 0.34

OE 0.86 (0.47–1.64)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.18Z-score

OE missense 1.05 (0.91–1.21)

128 obs / 122.4 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.86 (0.47–1.64)

0≤0.351.4

Missense OE?1.05 (0.91–1.21)

0≤0.61.4

Synonymous OE?0.96

0≤1.21.6

LoF obs/exp: 6 / 7.0Missense obs/exp: 128 / 122.4Syn Z: 0.22

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveTMEM126B-related muscle weakness and isolated complex I deficiencyLOFAR

This gene — mechanism propensity

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

0.7229th %ile

GOF

0.4875th %ile

LOF

0.3549th %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

135 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic9

Likely Pathogenic8

VUS57

Likely Benign38

Benign12

Conflicting4

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	9	0	0	0	9
Likely Pathogenic	6	2	0	0	8
VUS	2	51	4	0	57
Likely Benign	0	10	15	13	38
Benign	0	2	10	0	12
Conflicting	—				4
Total	17	65	29	13	128

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

View in ClinVar →

22 pathogenic / likely-pathogenic (of 28) ClinVar copy-number / structural variants overlap TMEM126B — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →