TMPRSS6 p.Pro540=
c.1620G>A · VCV4947741
Likely benign
Single submitter
Classification
Likely benign
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 1 submitter
gnomAD v4.1
Rare
very rare (popmax 0.00446%, eas)
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 -3.5 |
| Overall | ||
| CADD | 0.36 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.00446%
East Asian · 2/44,848 alleles
Filtering AF
0.00223%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.00198%
Overall
0.00267%
43/1,613,250 alleles · very rare
exomes 43/1,461,184 · genomes 0/152,066 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| East Asiangrpmax | 0.00446% | 22,424 |
| Admixed American | 0.00333% | 30,002 |
| European (non-Finnish) | 0.00305% | 32,777 |
| Remaining individualsnot grpmax-eligible | 0.0016% | 62,490 |
| African / African-American | 0.00133% | 74,946 |
| South Asian | 0.0011% | 91,066 |
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.Pro540=
- Coding
- c.1620G>A
- MANE Select
- NM_001374504
- Type
- single nucleotide variant
- Location
- chr22:37070968 (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 540
- the ldl-receptor class a 3 domain
Similar variants
- TMPRSS6 p.Pro540Gln Uncertain significance ★ ⚠ same residue
- TMPRSS6 p.Pro540Leu Uncertain significance ★ same residue
- 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
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-pro540 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown