TMPRSS3 p.Ser223=
c.669C>T · rs369273878 · VCV1914163
Uncertain significance
Single submitter
Classification
Uncertain significance
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 1 submitter
gnomAD v4.1
Rare
very rare (popmax 0.00229%, nfe)
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal. | ||
| Splicing | ||
| SpliceAI | Δ0.25 | acceptor gain · deltas |
|---|---|---|
| Pangolin | Δ0.26 | gain · loss 0.00 · agrees with SpliceAI · independent |
| Constraint at this position | ||
| Conservation | phyloP 0.54 | GERP -5, phastCons 0.044 |
| Overall | ||
| CADD | 9.854 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.00229%
European (non-Finnish) · 27/1,180,056 alleles
Filtering AF
0.00157%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.00134%
Overall
0.00173%
28/1,614,096 alleles · very rare
exomes 27/1,461,848 · genomes 1/152,248 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| European (non-Finnish)grpmax | 0.00229% | 43,706 |
| Remaining individualsnot grpmax-eligible | 0.0016% | 62,490 |
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.Ser223=
- Coding
- c.669C>T
- MANE Select
- NM_001256317
- dbSNP
- rs369273878
- Type
- single nucleotide variant
- Location
- chr21:42383146 (GRCh38)
- Gene constraint
- LOEUF 1.106 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
- Structure
- AlphaFold pLDDT 87.09
- Residue 223
- the peptidase s1 domain
Similar variants
- 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
- TMPRSS3 p.Ala306Val 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-ser223 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown