TMEM63A

Chr 1AD

transmembrane protein 63A

Also known as: HLD19, KIAA0792, hTMEM63A

NCBI Gene: 9725ENSG00000196187UniProt: O94886

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]

Primary Disease Associations & Inheritance

Leukodystrophy, hypomyelinating, 19, transient infantileMIM #618688
AD
305
ClinVar variants
13
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— TMEM63A
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
13 Pathogenic / Likely Pathogenic· 98 VUS of 305 total submissions
Some data sources returned errors (1)

clinvar: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esearch.fcgi

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.83LOEUF
pLI 0.000
Z-score 2.43
OE 0.60 (0.44–0.83)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
1.24Z-score
OE missense 0.84 (0.77–0.91)
384 obs / 459.0 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.60 (0.44–0.83)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.84 (0.77–0.91)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.94
0≤1.21.6
LoF obs/exp: 26 / 43.2Missense obs/exp: 384 / 459.0Syn Z: 0.63

ClinVar Variant Classifications

305 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic8
Likely Pathogenic5
VUS98
Likely Benign38
Benign2
Conflicting1
8
Pathogenic
5
Likely Pathogenic
98
VUS
38
Likely Benign
2
Benign
1
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
8
0
8
Likely Pathogenic
1
4
0
0
5
VUS
5
89
4
0
98
Likely Benign
1
25
2
10
38
Benign
0
2
0
0
2
Conflicting
—1
Total71201410152

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

View in ClinVar →

Protein Context — Lollipop Plot

TMEM63A · protein map & ClinVar variants

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

Gene2Phenotype Curations

TMEM63A-related transient hypomyelination during infancy

strong
ADUndeterminedAltered Gene Product Structure
Dev. Disorders
G2P ↗
missense variantinframe deletioninframe insertion

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Leukodystrophy, hypomyelinating, 19, transient infantile

MIM #618688

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
TMEM63A, associated with hypomyelinating leukodystrophies, is an evolutionarily conserved regulator of myelination.
Halford J et al.·Proc Natl Acad Sci U S A
2025
TMEM63 mechanosensitive ion channels: Activation mechanisms, biological functions and human genetic disorders.
Chen X et al.·Biochem Biophys Res Commun
2023Review
A novel de novo TMEM63A variant in a patient with severe hypomyelination and global developmental delay.
Fukumura S et al.·Brain Dev
2022Case report
Deep learning analyses of splicing variants identify the link of PCP4 with amyotrophic lateral sclerosis.
Tang X et al.·Brain
2025
A novel heterozygous TMEM63A variant in a familial case with early onset nystagmus, severe hypomyelination, and a favorable adult prognosis.
Yoneno S et al.·J Hum Genet
2024Case report
A TMEM63A Nonsense Heterozygous Variant Linked to Infantile Transient Hypomyelinating Leukodystrophy Type 19?
Siori D et al.·Genes (Basel)
2024Case report
Overview of genetic variants in a cohort of Iranian patients with leukodystrophy.
Fathi M et al.·Sci Rep
2025Review
Heterozygous Variants in the Mechanosensitive Ion Channel TMEM63A Result in Transient Hypomyelination during Infancy.
Yan H et al.·Am J Hum Genet
2019Case report
Spinal cord involvement and paroxysmal events in "Infantile Onset Transient Hypomyelination" due to TMEM63A mutation.
Tonduti D et al.·J Hum Genet
2021Case report
Genetic analysis of 20 patients with hypomyelinating leukodystrophy by trio-based whole-exome sequencing.
Yan H et al.·J Hum Genet
2021Cohort
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools