TMEM63C

Chr 14AR

transmembrane protein 63C

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

NCBI Gene: 57156 ENSG00000165548 UniProt: Q9P1W3 OMIM: 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.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

Enables calcium-activated cation channel activity. Involved in monoatomic cation transport. Predicted to be located in endoplasmic reticulum membrane. Predicted to be active in plasma membrane. Implicated in hereditary spastic paraplegia 87. Biomarker of focal segmental glomerulosclerosis. [provided by Alliance of Genome Resources, Apr 2025]

OMIM ResearchGenerating clinical summary…

MultiplemechanismARLOEUF 0.401 OMIM phenotype

Clinical Summary— TMEM63C

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.23) despite low pLI — interpret in context.

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ClinVar Variants

4 unique Pathogenic / Likely Pathogenic· 92 VUS of 122 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 OE?0.23 (0.14–0.40)

0≤0.351.4

Missense OE?0.74 (0.68–0.80)

0≤0.61.4

Synonymous OE?0.98

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

This gene — mechanism propensity

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

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

122 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic4

VUS92

Likely Benign3

Conflicting1

Pathogenic

VUS

Likely Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	4	0	0	0	4
Likely Pathogenic	0	0	0	0	0
VUS	0	92	0	0	92
Likely Benign	0	1	0	2	3
Benign	0	0	0	0	0
Conflicting	—				1
Total	4	93	0	2	100

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

View in ClinVar →

16 pathogenic / likely-pathogenic (of 20) ClinVar copy-number / structural variants overlap TMEM63C — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →