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TMEM249

Chr 8

catsper channel auxiliary subunit theta

Also known as: C8ORFK29, TMEM249

NCBI Gene: 340393 UniProt: Q2WGJ8

The protein is an auxiliary component of the CatSper complex that is involved in sperm cell hyperactivation and is predicted to be located in the sperm principal piece. Based on the available data, no human diseases have been definitively associated with TMEM249 mutations. The gene shows moderate tolerance to loss-of-function variants (pLI 0.10, LOEUF 0.85), suggesting it may not be highly constrained in humans.

ResearchSummary from RefSeq, UniProt

Predicted to be located in sperm principal piece. Predicted to be part of CatSper complex. [provided by Alliance of Genome Resources, Jul 2025]

ResearchGenerating clinical summary…

DNmechanismLOEUF 0.85

Clinical Summary— TMEM249

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.33) despite low pLI — interpret in context.

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ClinVar Variants

1 VUS of 1 total submissions

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

ensembl: Error: Ensembl fetch failed: 400 for /lookup/symbol/homo_sapiens/TMEM249?content-type=application/json&expand=1

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.85LOEUF

pLI 0.105

Z-score 1.88

OE 0.33 (0.15–0.85)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.88Z-score

OE missense 0.80 (0.69–0.93)

120 obs / 150.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.33 (0.15–0.85)

0≤0.351.4

Missense OE?0.80 (0.69–0.93)

0≤0.61.4

Synonymous OE?1.05

0≤1.21.6

LoF obs/exp: 3 / 9.1Missense obs/exp: 120 / 150.6Syn Z: -0.31

This gene — mechanism propensity

0.6648th %ile

GOF

0.6149th %ile

LOF

0.3065th %ile

The highest-scoring mechanism for this gene is dominant-negative.

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

1 submitted variants in ClinVar

ClinVar

Classification Summary

VUS1

VUS

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Total
Pathogenic	0	0
Likely Pathogenic	0	0
VUS	1	1
Likely Benign	0	0
Benign	0	0
Total	1	1

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

View in ClinVar →

24 pathogenic / likely-pathogenic (of 34) ClinVar copy-number / structural variants overlap TMEM249 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →