TMEM63C

Chr 14

transmembrane protein 63C

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

NCBI Gene: 57156 ENSG00000165548 UniProt: Q9P1W3

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.

ResearchSummary from RefSeq, OMIM, UniProt

Enables calcium-activated cation channel activity. Involved in monoatomic cation transport. Located in lysosomal membrane and plasma membrane. Implicated in hereditary spastic paraplegia 87. Biomarker of focal segmental glomerulosclerosis. [provided by Alliance of Genome Resources, Jun 2026]

ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtSpastic paraplegia 87, autosomal recessive

Clinical highlights

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.40

LOEUF

Multiple*

Mechanism· predicted

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

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

Background carrier burden — how many people carry a rare variant somewhere in TMEM63C?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 70

875 rare PASS variants

Rare truncating (LoF)

1 in 6,800

56 rare PASS variants

Rare synonymous (reference)

1 in 76

406 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for TMEM63C. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 110	1 in 6,900
South Asian	~43k	1 in 70	none seen
Remaining (unassigned)	~30k	1 in 82	≈ 1 in 15,000
European (Finnish)	~27k	1 in 180	≈ 1 in 26,000
Admixed American	~22k	1 in 57	1 in 2,500
African / African American	~21k	1 in 80	≈ 1 in 4,300
East Asian	~20k	1 in 57	≈ 1 in 9,900
Ashkenazi Jewish	~13k	1 in 570	none seen
Middle Eastern	~2,884	1 in 120	≈ 1 in 2,900

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 22 of 22 coding exons well covered in gnomAD exomes. Genomes: 21 of 22 (exon 9 below).? see exons ↓