Is HFE p.Pro7Arg (c.20C>G) pathogenic?

HFE p.Pro7Arg (c.20C>G) is classified Uncertain significance in HFE (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-01-02). AlphaMissense: likely benign (0.0994); Ultra-rare (popmax 0.0154%, sas); Associated with hereditary hemochromatosis.

What condition is associated with HFE p.Pro7Arg (c.20C>G)?

HFE p.Pro7Arg (c.20C>G) is associated with hereditary hemochromatosis (ClinVar).

How common is HFE p.Pro7Arg (c.20C>G) in the general population?

HFE p.Pro7Arg (c.20C>G) is ultra-rare (popmax 0.0154%, sas) (gnomAD).

What do computational predictors say about HFE p.Pro7Arg (c.20C>G)?

AlphaMissense predicts likely benign (score 0.0994) — an in-silico prediction, not a clinical call.

HFE p.Pro7Arg

c.20C>G · rs766754409 · VCV1317189

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0994 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0154%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary hemochromatosis

Computational evidence

Protein change
AlphaMissense	0.0994	likely benign
REVEL	0.037	moderately benign-leaning
SaProt	LLR -6.86	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 -0.56	GERP -2.2
Regional constraint	o/e 0.88	unconstrained · MANE · 4,082 bp · p 0.059 · regional, not allelic
Overall
CADD	15.91	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 0.0154% South Asian · 14/91,084 alleles

Filtering AF 0.00919% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00735%

Overall 0.00235% 38/1,613,966 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0154%	6,506
Remaining individualsnot grpmax-eligible	0.008%	12,496
East Asian	0.00446%	22,445
European (non-Finnish)	0.00144%	69,412

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.Pro7Arg
Coding: c.20C>G
MANE Select: NM_000410
dbSNP: rs766754409
Type: single nucleotide variant
Location: chr6:26087460 (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

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

Similar variants

HFE p.Pro7= Conflicting classifications of pathogenicity ★ 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 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

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-pro7arg (accessed [today's date]).

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