HFE p.Pro301=
c.903G>A · rs372856303 · VCV1121633
Likely benign
Multiple submitters
Classification
Likely benign
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 2 submitters
gnomAD v4.1
Rare
very rare (popmax 0.01%, amr)
Conditions
1
hereditary hemochromatosis
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 -2.3 | GERP -4.9 |
| Overall | ||
| CADD | 1.703 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.01%
Admixed American · 6/60,028 alleles
Filtering AF
0.00428%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.00295%
Overall
0.00173%
28/1,614,070 alleles · very rare
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Admixed Americangrpmax | 0.01% | 10,005 |
| African / African-American | 0.00667% | 15,003 |
| South Asian | 0.00659% | 15,182 |
| East Asian | 0.00223% | 44,888 |
| Remaining individualsnot grpmax-eligible | 0.0016% | 62,502 |
| European (non-Finnish) | 0.000763% | 131,104 |
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
- HFE
- Protein
- p.Pro301=
- Coding
- c.903G>A
- MANE Select
- NM_000410
- dbSNP
- rs372856303
- Type
- single nucleotide variant
- Location
- chr6:26093129 (GRCh38)
- Gene constraint
- LOEUF 1.037 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
- Structure
- AlphaFold pLDDT 88.62 · 2 PDB
- Residue 301
- the 'connecting peptide' region
Similar variants
- HFE c.1006+1G>A Pathogenic/Likely pathogenic ★★ same condition
- HFE c.616+1G>A Pathogenic/Likely pathogenic ★★ same condition
- HFE c.616+1G>T Pathogenic ★★ same condition
- HFE c.76+2T>C Likely pathogenic ★★ same condition
- HFE p.Gln283Pro Pathogenic/Likely pathogenic ★★ ⚠ same condition
- HFE p.Glu298Ter Pathogenic/Likely pathogenic ★★ same condition
- HFE p.Leu183Pro Pathogenic/Likely pathogenic ★★ same condition
- HFE p.Lys254Ter Pathogenic/Likely pathogenic ★★ 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/hfe-p-pro301 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown