TMPRSS3 p.Ala417=
c.1251G>A · rs756106839 · VCV2712249
Likely benign
Single submitter
Classification
Likely benign
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 1 submitter
gnomAD v4.1
Rare
very rare (popmax 0.00878%, sas)
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
|---|---|---|
| Constraint at this position | ||
| Conservation | phyloP -7.3 | GERP -5 |
| Overall | ||
| CADD | 0.863 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.00878%
South Asian · 8/91,078 alleles
Filtering AF
0.00437%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.00312%
Overall
0.00211%
34/1,613,784 alleles · very rare
exomes 28/1,461,662 · genomes 6/152,122 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| South Asiangrpmax | 0.00878% | 11,385 |
| Remaining individualsnot grpmax-eligible | 0.008% | 12,496 |
| East Asian | 0.00223% | 44,872 |
| Admixed American | 0.00167% | 60,002 |
| European (non-Finnish) | 0.00161% | 62,106 |
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
- TMPRSS3
- Protein
- p.Ala417=
- Coding
- c.1251G>A
- MANE Select
- NM_001256317
- dbSNP
- rs756106839
- Type
- single nucleotide variant
- Location
- chr21:42375809 (GRCh38)
- Gene constraint
- LOEUF 1.106 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
- Structure
- AlphaFold pLDDT 87.09
- Residue 417
- the peptidase s1 domain
Similar variants
- TMPRSS3 p.Ala417Val Uncertain significance ★★ ⚠ same residue
- TMPRSS3 c.1049-4G>A Likely pathogenic ★★ same type
- TMPRSS3 c.206-2A>G Likely pathogenic ★★ same type
- TMPRSS3 c.323-6G>A Pathogenic/Likely pathogenic ★★ same type
- TMPRSS3 c.446+1G>T Likely pathogenic ★★ same type
- TMPRSS3 c.573-1G>A Likely pathogenic ★★ same type
- TMPRSS3 p.Ala138Glu Pathogenic/Likely pathogenic ★★ same type
- TMPRSS3 p.Ala306Thr Pathogenic/Likely pathogenic ★★ 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/tmprss3-p-ala417 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown