TMPRSS6 p.Ala769=
c.2307G>A · VCV4692151
Likely benign
Single submitter
Classification
Likely benign
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 1 submitter
gnomAD v4.1
Rare
ultra-rare (popmax 0.0209%, 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 -14 | GERP -4.5 |
| Overall | ||
| CADD | 4.306 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.0209%
South Asian · 19/91,084 alleles
Filtering AF
0.0136%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.0114%
Overall
0.00242%
39/1,613,052 alleles · ultra-rare
| Ancestry group | Frequency | 1 in |
|---|---|---|
| South Asiangrpmax | 0.0209% | 4,794 |
| East Asian | 0.00891% | 11,223 |
| African / African-American | 0.00667% | 14,989 |
| Remaining individualsnot grpmax-eligible | 0.0016% | 62,470 |
| European (non-Finnish) | 0.000847% | 118,000 |
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
- TMPRSS6
- Protein
- p.Ala769=
- Coding
- c.2307G>A
- MANE Select
- NM_001374504
- Type
- single nucleotide variant
- Location
- chr22:37066182 (GRCh38)
- Gene constraint
- LOEUF 0.821 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
- Structure
- AlphaFold pLDDT 84.69 · 1 PDB
- Residue 769
- the peptidase s1 domain; a β-strand; a disulfide bond
Similar variants
- TMPRSS6 c.1342+1G>A Pathogenic/Likely pathogenic ★★ same type
- TMPRSS6 p.Arg590Ter Pathogenic/Likely pathogenic ★★ same type
- TMPRSS6 p.Asp512Asn Likely pathogenic ★★ same type
- TMPRSS6 p.Gly433Arg Pathogenic/Likely pathogenic ★★ ⚠ same type
- TMPRSS6 p.Lys70Ter Likely pathogenic ★★ same type
- TMPRSS6 p.Ser552Ter Pathogenic ★★ same type
- TMPRSS6 p.Tyr346Ter Likely pathogenic ★★ same type
- TMPRSS6 p.Ala164Thr 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/tmprss6-p-ala769 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown