TMPRSS6 p.Pro668=
c.2004G>A · rs565997258 · VCV902219
Uncertain significance
Single submitter
Classification
Uncertain significance
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 1 submitter
gnomAD v4.1
Rare
very rare (popmax 0.00402%, afr)
Conditions
1
microcytic anemia
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal. | ||
| Splicing | ||
| SpliceAI | Δ0.23 | donor gain · deltas |
|---|---|---|
| Constraint at this position | ||
| Conservation | phyloP -10 | GERP -4.2 |
| Overall | ||
| CADD | 9.046 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.00402%
African / African-American · 3/74,552 alleles
Filtering AF
0.00107%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.000496%
Overall
0.000376%
6/1,594,228 alleles · very rare
| Ancestry group | Frequency | 1 in |
|---|---|---|
| African / African-Americangrpmax | 0.00402% | 24,851 |
| South Asian | 0.00227% | 44,117 |
| Remaining individualsnot grpmax-eligible | 0.00162% | 61,672 |
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.Pro668=
- Coding
- c.2004G>A
- MANE Select
- NM_001374504
- dbSNP
- rs565997258
- Type
- single nucleotide variant
- Location
- chr22:37069182 (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 668
- the peptidase s1 domain; an active site
Similar variants
- TMPRSS6 p.Pro668Ala Uncertain significance ★ ⚠ same residue
- TMPRSS6 p.Arg590Ter Pathogenic/Likely pathogenic ★★ same condition
- TMPRSS6 p.Asp512Asn Likely pathogenic ★★ same condition
- TMPRSS6 p.Ala700Val Uncertain significance ★★ ⚠ same condition
- TMPRSS6 p.Arg43Cys Uncertain significance ★★ ⚠ same condition
- TMPRSS6 p.Arg545Trp Uncertain significance ★★ ⚠ same condition
- TMPRSS6 p.Arg735His Uncertain significance ★★ ⚠ same condition
- TMPRSS6 p.Arg96His Uncertain significance ★★ ⚠ 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/tmprss6-p-pro668 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown