TMPRSS6 p.Cys480=
c.1440C>T · rs546574834 · VCV899477
Conflicting classifications of pathogenicity
Conflicting submitters
Classification
Conflicting classifications of pathogenicity
ClinVar
Review
Conflicting submitters ★☆☆☆
ClinVar · 6 submitters
gnomAD v4.1
Rare
low-frequency (popmax 1.55%, sas)
Conditions
1
microcytic anemia
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 -13 | GERP -3.7 |
| Overall | ||
| CADD | 0.039 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
1.55%
South Asian · 1,416/91,064 alleles
Filtering AF
1.49%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 1.46%
Overall
0.0924%
1,492/1,613,972 alleles · low-frequency
| Ancestry group | Frequency | 1 in |
|---|---|---|
| South Asiangrpmax | 1.55% | 64 |
| Remaining individualsnot grpmax-eligible | 0.0768% | 1,302 |
| Middle Eastern | 0.0495% | 2,020 |
| East Asian | 0.00891% | 11,222 |
| African / African-American | 0.004% | 25,017 |
| Ashkenazi Jewishnot grpmax-eligible | 0.00338% | 29,594 |
| Admixed American | 0.00167% | 60,014 |
| European (non-Finnish) | 0.00136% | 73,741 |
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.Cys480=
- Coding
- c.1440C>T
- MANE Select
- NM_001374504
- dbSNP
- rs546574834
- Type
- single nucleotide variant
- Location
- chr22:37074611 (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 480
- a disulfide bond; the ldl-receptor class a 1 domain
Similar variants
- 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
- TMPRSS6 p.Glu151Lys 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-cys480 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown