Is HFE p.Val256Ile (c.766G>A) pathogenic?

HFE p.Val256Ile (c.766G>A) is classified Uncertain significance in HFE (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-02-08). AlphaMissense: likely benign (0.0774); Very rare (popmax 0.00356%, nfe); Associated with hereditary hemochromatosis.

What condition is associated with HFE p.Val256Ile (c.766G>A)?

HFE p.Val256Ile (c.766G>A) is associated with hereditary hemochromatosis, Alzheimer disease type 1, familial porphyria cutanea tarda (ClinVar).

How common is HFE p.Val256Ile (c.766G>A) in the general population?

HFE p.Val256Ile (c.766G>A) is very rare (popmax 0.00356%, nfe) (gnomAD).

What do computational predictors say about HFE p.Val256Ile (c.766G>A)?

AlphaMissense predicts likely benign (score 0.0774) — an in-silico prediction, not a clinical call.

HFE p.Val256Ile

c.766G>A · rs202068193 · VCV461194

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0774 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00356%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary hemochromatosis

Computational evidence

Protein change
AlphaMissense	0.0774	likely benign
REVEL	0.067	moderately benign-leaning
SaProt	LLR -5.78	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.1	phastCons 0.95
Regional constraint	o/e 0.93	unconstrained · MANE · 2,652 bp · p 0.31 · regional, not allelic
Overall
CADD	10.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00356% European (non-Finnish) · 42/1,180,056 alleles

Filtering AF 0.00267% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00236%

Overall 0.00279% 45/1,614,110 alleles · very rare exomes 43/1,461,892 · genomes 2/152,218 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00356%	28,097
Finnishnot grpmax-eligible	0.00312%	32,022
Admixed American	0.00167%	60,010

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.Val256Ile
Coding: c.766G>A
MANE Select: NM_000410
dbSNP: rs202068193
Type: single nucleotide variant
Location: chr6:26092834 (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 256: the ig-like c1-type domain; a β-strand; the 'alpha-3' region

Full HFE gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary hemochromatosis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Alzheimer disease type 1 familial porphyria cutanea tarda variegate porphyria microvascular complications of diabetes, susceptibility to, 7 hemochromatosis 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-val256ile (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown