TMC8 p.Ile254=
c.762C>T · rs376868222 · VCV764401
Likely benign
Single submitter
Classification
Likely benign
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 1 submitter
gnomAD v4.1
Rare
very rare (popmax 0.00266%, afr)
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal. | ||
| Splicing | ||
| SpliceAI | Δ0.27 | acceptor gain · deltas |
|---|---|---|
| Constraint at this position | ||
| Conservation | phyloP 3.7 | GERP 1.2, phastCons 1 |
| Overall | ||
| CADD | 17.24 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.00266%
African / African-American · 2/75,072 alleles
Filtering AF
0.000442%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.000166%
Overall
0.000124%
2/1,613,648 alleles · very rare
exomes 2/1,461,282 · genomes 0/152,366 · joint denominator
Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.
Variant & gene context
- Gene
- TMC8
- Protein
- p.Ile254=
- Coding
- c.762C>T
- MANE Select
- NM_152468
- dbSNP
- rs376868222
- Type
- single nucleotide variant
- Location
- chr17:78133946 (GRCh38)
- Gene constraint
- LOEUF 1.201 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
- Structure
- AlphaFold pLDDT 76.77
Similar variants
- TMC8 c.1824-1G>C Pathogenic/Likely pathogenic ★★ same type
- TMC8 c.449-1G>T Likely pathogenic ★★ same type
- TMC8 p.Arg190Ter Pathogenic ★★ same type
- TMC8 p.Ala188Val Uncertain significance ★★ ⚠ same type
- TMC8 p.Ala290Thr Uncertain significance ★★ ⚠ same type
- TMC8 p.Ala313Val Uncertain significance ★★ ⚠ same type
- TMC8 p.Ala316Thr Uncertain significance ★★ ⚠ same type
- TMC8 p.Ala345Thr Uncertain significance ★★ ⚠ same type
Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →
Cite Sugi Variant
Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/tmc8-p-ile254 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown