TMEM63C

Chr 14AR

transmembrane protein 63C

Also known as: C14orf171, CSC1, SPG87, hTMEM63C, hsCSC1

NCBI Gene: 57156ENSG00000165548UniProt: Q9P1W3OMIM: 619953

TMEM63C encodes an osmosensitive cation channel that is activated by hypotonic stress and is enriched at mitochondria-ER contact sites where it regulates organelle morphology and mitochondrial function in motor neuron axons. Biallelic mutations cause spastic paraplegia 87, an autosomal recessive disorder affecting the corticospinal tracts. The gene shows moderate constraint against loss-of-function variants (LOEUF 0.398), and the protein is also required for kidney glomerular filtration barrier integrity.

OMIMResearchSummary from RefSeq, OMIM, UniProt
MultiplemechanismARLOEUF 0.401 OMIM phenotype
Clinical Summary— TMEM63C
⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.23) despite low pLI — interpret in context.
📋
ClinVar Variants
20 unique Pathogenic / Likely Pathogenic· 95 VUS of 141 total submissions
Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint
0.40LOEUF
pLI 0.243
Z-score 4.63
OE 0.23 (0.14–0.40)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint
2.07Z-score
OE missense 0.74 (0.68–0.80)
360 obs / 488.5 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios
LoF OE0.23 (0.14–0.40)
0≤0.351.4
Missense OE0.74 (0.68–0.80)
0≤0.61.4
Synonymous OE0.98
0≤1.21.6
LoF obs/exp: 10 / 42.6Missense obs/exp: 360 / 488.5Syn Z: 0.17
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
moderateTMEM63C-related hereditary spastic paraplegiaOTHERAR

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

DN
0.6161th %ile
GOF
0.76top 25%
LOF
0.2775th %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

141 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic17
Likely Pathogenic3
VUS95
Likely Benign3
Conflicting1
17
Pathogenic
3
Likely Pathogenic
95
VUS
3
Likely Benign
1
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
4
0
13
0
17
Likely Pathogenic
0
0
3
0
3
VUS
0
91
4
0
95
Likely Benign
0
1
0
2
3
Benign
0
0
0
0
0
Conflicting
—1
Total492202119

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

View in ClinVar →

Protein Context — Lollipop Plot

TMEM63C · protein map & ClinVar variants

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

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 2 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients