TMEM63A

Chr 1AD

transmembrane protein 63A

Also known as: HLD19, KIAA0792, hTMEM63A

NCBI Gene: 9725 ENSG00000196187 UniProt: O94886 OMIM: 618685

TMEM63A encodes a mechanosensitive cation channel that regulates lysosomal morphology and is essential for surfactant secretion in lung alveolar cells, playing a critical role in the baby's first breath and lifelong respiration. Mutations cause hypomyelinating leukodystrophy 19 with transient infantile onset, affecting both the central nervous system and respiratory function. The condition follows autosomal dominant inheritance, and the gene shows very low constraint against loss-of-function variants.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

Enables mechanosensitive monoatomic ion channel activity. Predicted to be involved in surfactant secretion. Located in bounding membrane of organelle; centriolar satellite; and plasma membrane. Implicated in hypomyelinating leukodystrophy 19. [provided by Alliance of Genome Resources, Apr 2025]

OMIM ResearchGenerating clinical summary…

MultiplemechanismADLOEUF 0.831 OMIM phenotype

Clinical Summary— TMEM63A

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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

9 unique Pathogenic / Likely Pathogenic· 139 VUS of 271 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?

0.83LOEUF

pLI 0.000

Z-score 2.43

OE 0.60 (0.44–0.83)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.24Z-score

OE missense 0.84 (0.77–0.91)

384 obs / 459.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.60 (0.44–0.83)

0≤0.351.4

Missense OE?0.84 (0.77–0.91)

0≤0.61.4

Synonymous OE?0.94

0≤1.21.6

LoF obs/exp: 26 / 43.2Missense obs/exp: 384 / 459.0Syn Z: 0.63

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongTMEM63A-related transient hypomyelination during infancyOTHERAD

This gene — mechanism propensity

0.6455th %ile

GOF

0.76top 25%

LOF

0.2677th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

271 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic3

Likely Pathogenic6

VUS139

Likely Benign44

Benign22

Conflicting4

Pathogenic

Likely Pathogenic

139

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	3	0	0	3
Likely Pathogenic	1	5	0	0	6
VUS	8	127	4	0	139
Likely Benign	1	30	2	11	44
Benign	0	6	7	9	22
Conflicting	—				4
Total	10	171	13	20	218

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

View in ClinVar →

31 pathogenic / likely-pathogenic (of 39) ClinVar copy-number / structural variants overlap TMEM63A — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →