Is HFE p.Pro208Ala (c.622C>G) pathogenic?

HFE p.Pro208Ala (c.622C>G) is classified Uncertain significance in HFE (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-03-04). AlphaMissense: likely pathogenic (0.6102); Very rare (popmax 8.47e-05%, nfe).

How common is HFE p.Pro208Ala (c.622C>G) in the general population?

HFE p.Pro208Ala (c.622C>G) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about HFE p.Pro208Ala (c.622C>G)?

AlphaMissense predicts likely pathogenic (score 0.6102) — an in-silico prediction, not a clinical call.

HFE p.Pro208Ala

c.622C>G · rs866376221 · VCV2692107

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6102 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6102	likely pathogenic
REVEL	0.168	moderately benign-leaning
SaProt	LLR -10.79	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.6	phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 2,652 bp · p 0.31 · regional, not allelic
Overall
CADD	19.12	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,042 alleles

Overall 6.2e-05% 1/1,614,204 alleles · very rare exomes 1/1,461,890 · genomes 0/152,314 · joint denominator

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.Pro208Ala
Coding: c.622C>G
MANE Select: NM_000410
dbSNP: rs866376221
Type: single nucleotide variant
Location: chr6:26092690 (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 208: the ig-like c1-type domain; the 'alpha-3' region

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

Similar variants

HFE p.Pro208Thr Uncertain significance ★ ⚠ same residue
HFE c.1006+1G>A Pathogenic/Likely pathogenic ★★ same type
HFE c.616+1G>A Pathogenic/Likely pathogenic ★★ same type
HFE c.616+1G>T Pathogenic ★★ same type
HFE c.76+2T>C Likely pathogenic ★★ same type
HFE p.Gln283Pro Pathogenic/Likely pathogenic ★★ ⚠ same type
HFE p.Glu298Ter Pathogenic/Likely pathogenic ★★ same type
HFE p.Leu183Pro Pathogenic/Likely pathogenic ★★ same type

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-pro208ala (accessed [today's date]).

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