Is HFE p.Phe326Ile (c.976T>A) pathogenic?

HFE p.Phe326Ile (c.976T>A) is classified Uncertain significance in HFE (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-02). AlphaMissense: likely benign (0.1237); Very rare (popmax 8.48e-05%, nfe); Associated with hemochromatosis type 1.

What condition is associated with HFE p.Phe326Ile (c.976T>A)?

HFE p.Phe326Ile (c.976T>A) is associated with hemochromatosis type 1 (ClinVar).

How common is HFE p.Phe326Ile (c.976T>A) in the general population?

HFE p.Phe326Ile (c.976T>A) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about HFE p.Phe326Ile (c.976T>A)?

AlphaMissense predicts likely benign (score 0.1237) — an in-silico prediction, not a clinical call.

HFE p.Phe326Ile

c.976T>A · rs1214213770 · VCV3233283

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1237 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hemochromatosis type 1

Computational evidence

Protein change
AlphaMissense	0.1237	likely benign
REVEL	0.062	moderately benign-leaning
SaProt	LLR -5.46	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 -0.15	GERP -4.4, phastCons 0.56
Regional constraint	o/e 0.93	unconstrained · MANE · 2,652 bp · p 0.31 · regional, not allelic
Overall
CADD	7.79	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 8.48e-05% European (non-Finnish) · 1/1,179,816 alleles

Overall 6.84e-05% 1/1,461,674 alleles · very rare

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.Phe326Ile
Coding: c.976T>A
MANE Select: NM_000410
dbSNP: rs1214213770
Type: single nucleotide variant
Location: chr6:26093202 (GRCh38)
Gene constraint: LOEUF 1.037 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 88.62 · 2 PDB

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

Disease context

hemochromatosis type 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

HFE p.Phe326= Likely benign ★ same residue
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 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-phe326ile (accessed [today's date]).

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