TMC8 p.Pro576=
c.1728G>A · rs753149174 · VCV712956
Likely benign
Multiple submitters
Classification
Likely benign
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 3 submitters
gnomAD v4.1
Rare
very rare (popmax 0.00549%, sas)
Conditions
2
Inborn genetic diseases
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| REVEL | 0.211 | benign-leaning |
|---|---|---|
| Splicing | ||
| SpliceAI | <0.2 | no splice effect predicted · four deltas, not one · how we know |
| Constraint at this position | ||
| Conservation | phyloP -9.8 | GERP -3.1 |
| Overall | ||
| CADD | 0.397 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.00549%
South Asian · 5/91,094 alleles
Filtering AF
0.0021%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.00136%
Overall
0.00118%
19/1,613,816 alleles · very rare
exomes 18/1,461,558 · genomes 1/152,258 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| South Asiangrpmax | 0.00549% | 18,219 |
| Admixed American | 0.00333% | 30,007 |
| East Asian | 0.00223% | 44,900 |
| Remaining individualsnot grpmax-eligible | 0.0016% | 62,484 |
| European (non-Finnish) | 0.000847% | 118,004 |
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.Pro576=
- Coding
- c.1728G>A
- MANE Select
- NM_152468
- dbSNP
- rs753149174
- Type
- single nucleotide variant
- Location
- chr17:78138637 (GRCh38)
- Gene constraint
- LOEUF 1.201 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
- Structure
- AlphaFold pLDDT 76.77
- Residue 576
- a UniProt-annotated variant site (in ev2)
Similar variants
- TMC8 p.Pro576Leu Uncertain significance ★ ⚠ same residue
- TMC8 c.1824-1G>C Pathogenic/Likely pathogenic ★★ same condition
- TMC8 c.449-1G>T Likely pathogenic ★★ same condition
- TMC8 p.Arg190Ter Pathogenic ★★ same condition
- TMC8 p.Ala188Val Uncertain significance ★★ ⚠ same condition
- TMC8 p.Ala290Thr Uncertain significance ★★ ⚠ same condition
- TMC8 p.Ala313Val Uncertain significance ★★ ⚠ same condition
- TMC8 p.Ala316Thr Uncertain significance ★★ ⚠ same condition
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-pro576 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown