Is HFE p.Arg6Ser (c.18G>C) pathogenic?

HFE p.Arg6Ser (c.18G>C) is classified Uncertain significance in HFE (ClinVar, Multiple submitters, 14 submitters; last evaluated 2026-04-13). AlphaMissense: likely benign (0.2442); Rare (popmax 0.128%, nfe); Associated with hemochromatosis type 1.

What condition is associated with HFE p.Arg6Ser (c.18G>C)?

HFE p.Arg6Ser (c.18G>C) is associated with hemochromatosis type 1, hereditary hemochromatosis, Alzheimer disease type 1 (ClinVar).

How common is HFE p.Arg6Ser (c.18G>C) in the general population?

HFE p.Arg6Ser (c.18G>C) is rare (popmax 0.128%, nfe) (gnomAD).

What do computational predictors say about HFE p.Arg6Ser (c.18G>C)?

AlphaMissense predicts likely benign (score 0.2442) — an in-silico prediction, not a clinical call.

HFE p.Arg6Ser

c.18G>C · rs149342416 · VCV216425

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 14 submitters

AlphaMissense

likely benign

0.2442 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.128%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hemochromatosis type 1

Computational evidence

Protein change
AlphaMissense	0.2442	likely benign
REVEL	0.221	benign-leaning
SaProt	LLR -6.20	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 2	GERP -2.2, phastCons 0.081
Regional constraint	o/e 0.88	unconstrained · MANE · 4,082 bp · p 0.059 · regional, not allelic
Overall
CADD	15.79	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 0.128% European (non-Finnish) · 1,512/1,180,002 alleles

Filtering AF 0.123% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.121%

Overall 0.103% 1,658/1,614,002 alleles · rare exomes 1,552/1,461,786 · genomes 106/152,216 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.128%	780
Remaining individualsnot grpmax-eligible	0.109%	919
Admixed American	0.0633%	1,579
African / African-American	0.0387%	2,584
Middle Eastern	0.0165%	6,068
Finnishnot grpmax-eligible	0.0156%	6,401

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.Arg6Ser
Coding: c.18G>C
MANE Select: NM_000410
dbSNP: rs149342416
Type: single nucleotide variant
Location: chr6:26087458 (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 6: a UniProt-annotated variant site (in hfe1; uncertain significance)

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

Also linked: hereditary hemochromatosis Alzheimer disease type 1 familial porphyria cutanea tarda variegate porphyria microvascular complications of diabetes, susceptibility to, 7

Similar variants

HFE p.Arg6Thr Uncertain significance ★ ⚠ 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-arg6ser (accessed [today's date]).

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