HFE p.His63=
c.189T>C · rs147426902 · VCV219411
Benign/Likely benign
Multiple submitters
Classification
Benign/Likely benign
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 7 submitters
gnomAD v4.1
Rare
rare (popmax 0.953%, afr)
Conditions
2
hemochromatosis type 1
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| Splicing | ||
| SpliceAI | <0.2 | all four deltas below 0.2 · T>G here scores Δ0.30 · evaluated, not missing |
|---|---|---|
| Constraint at this position | ||
| Conservation | phyloP -5.3 | |
| Overall | ||
| CADD | 3.109 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.953%
African / African-American · 715/75,036 alleles
Filtering AF
0.895%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.872%
Overall
0.0488%
788/1,614,190 alleles · rare
| Ancestry group | Frequency | 1 in |
|---|---|---|
| African / African-Americangrpmax | 0.953% | 105 |
| Remaining individualsnot grpmax-eligible | 0.0544% | 1,838 |
| Admixed American | 0.0516% | 1,936 |
| South Asian | 0.00439% | 22,770 |
| European (non-Finnish) | 0.000339% | 295,011 |
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.His63=
- Coding
- c.189T>C
- MANE Select
- NM_000410
- dbSNP
- rs147426902
- Type
- single nucleotide variant
- Location
- chr6:26090953 (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 63
- a UniProt-annotated variant site (in hfe1; associated in cis with d-43 in one patient; also found in individuals with variegate porphyria; increased frequency among patients with diabetic nephropathy; low penetrance variant); a β-strand; the 'alpha-1' 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-his63 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown