Computational evidence
| Protein change | ||
| AlphaMissense | 0.2754 | likely benign |
|---|---|---|
| REVEL | 0.549 | indeterminate |
| SaProt | LLR -11.91 | damaging |
| ⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP 6.6 | phastCons 1 |
| Regional constraint | o/e 0.88 | unconstrained · MANE · 4,082 bp · p 0.059 · regional, not allelic |
| Overall | ||
| CADD | 25.1 | PHRED · no single calibrated threshold — expert panels disagree |
AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.
Population frequency
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Amishnot grpmax-eligible | 2.64% | 38 |
| Finnishnot grpmax-eligible | 2.21% | 45 |
| European (non-Finnish)grpmax | 1.63% | 61 |
| Remaining individualsnot grpmax-eligible | 1.09% | 92 |
| Admixed American | 0.523% | 191 |
| Ashkenazi Jewishnot grpmax-eligible | 0.301% | 333 |
| African / African-American | 0.253% | 395 |
| Middle Eastern | 0.099% | 1,010 |
| South Asian | 0.0988% | 1,012 |
| East Asian | 0.0178% | 5,609 |
Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.
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.Ser65Cys
- Coding
- c.193A>T
- MANE Select
- NM_000410
- dbSNP
- rs1800730
- Type
- single nucleotide variant
- Location
- chr6:26090957 (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 65
- a UniProt-annotated variant site (in hfe1; mild form); a β-strand; the 'alpha-1' region
Disease context
microvascular complications of diabetes, susceptibility to, 7 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatmentsAlso linked: Alzheimer diseasehereditary hemochromatosisAlzheimer disease type 1familial porphyria cutanea tardavariegate porphyriahemochromatosis type 1
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-ser65cys (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown