TMPRSS3 p.Gln227=
c.681G>A · rs201260442 · VCV340060
Conflicting classifications of pathogenicity
Conflicting submitters
Classification
Conflicting classifications of pathogenicity
ClinVar
Review
Conflicting submitters ★☆☆☆
ClinVar · 5 submitters
gnomAD v4.1
Rare
rare (popmax 0.675%, eas)
Conditions
1
autosomal recessive nonsyndromic hearing loss 8
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal. | ||
| Splicing | ||
| SpliceAI | Δ0.23 | acceptor loss · deltas |
|---|---|---|
| Constraint at this position | ||
| Conservation | phyloP 3.1 | GERP 2.5, phastCons 1 |
| Overall | ||
| CADD | 9.635 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.675%
East Asian · 303/44,886 alleles
Filtering AF
0.613%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.588%
Overall
0.0214%
345/1,614,216 alleles · rare
exomes 317/1,461,846 · genomes 28/152,370 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| East Asiangrpmax | 0.675% | 148 |
| Remaining individualsnot grpmax-eligible | 0.0288% | 3,473 |
| South Asian | 0.0165% | 6,073 |
| European (non-Finnish) | 0.000763% | 131,116 |
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.Gln227=
- Coding
- c.681G>A
- MANE Select
- NM_001256317
- dbSNP
- rs201260442
- Type
- single nucleotide variant
- Location
- chr21:42383134 (GRCh38)
- Gene constraint
- LOEUF 1.106 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
- Structure
- AlphaFold pLDDT 87.09
- Residue 227
- the peptidase s1 domain
Similar variants
- TMPRSS3 c.1049-4G>A Likely pathogenic ★★ same condition
- TMPRSS3 c.206-2A>G Likely pathogenic ★★ same condition
- TMPRSS3 c.323-6G>A Pathogenic/Likely pathogenic ★★ same condition
- TMPRSS3 c.446+1G>T Likely pathogenic ★★ same condition
- TMPRSS3 c.573-1G>A Likely pathogenic ★★ same condition
- TMPRSS3 p.Ala138Glu Pathogenic/Likely pathogenic ★★ same condition
- TMPRSS3 p.Ala306Thr Pathogenic/Likely pathogenic ★★ same condition
- TMPRSS3 p.Ala306Val Likely pathogenic ★★ 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/tmprss3-p-gln227 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown