Is HFE p.Trp74Ser (c.221G>C) pathogenic?

HFE p.Trp74Ser (c.221G>C) is classified Uncertain significance in HFE (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-09). AlphaMissense: likely pathogenic (0.6882); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with HFE p.Trp74Ser (c.221G>C)?

HFE p.Trp74Ser (c.221G>C) is associated with Inborn genetic diseases (ClinVar).

How common is HFE p.Trp74Ser (c.221G>C) in the general population?

HFE p.Trp74Ser (c.221G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about HFE p.Trp74Ser (c.221G>C)?

AlphaMissense predicts likely pathogenic (score 0.6882) — an in-silico prediction, not a clinical call.

HFE p.Trp74Ser

c.221G>C · VCV4621525

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6882 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.6882	likely pathogenic
REVEL	0.27	benign-leaning
SaProt	LLR -13.77	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 11	phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 4,082 bp · p 0.059 · regional, not allelic
Overall
CADD	24.7	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: HFE
Protein: p.Trp74Ser
Coding: c.221G>C
MANE Select: NM_000410
Type: single nucleotide variant
Location: chr6:26090985 (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 74: the 'alpha-1' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

HFE p.Arg67His Uncertain significance ★★ ⚠ same condition
HFE p.Asn130Ser Uncertain significance ★★ ⚠ same condition
HFE p.Gly334Cys Uncertain significance ★★ ⚠ same condition
HFE p.Gly337Val Uncertain significance ★★ ⚠ same condition
HFE p.Lys243Glu Uncertain significance ★★ ⚠ same condition
HFE p.Ala18Gly Uncertain significance ★ ⚠ same condition
HFE p.Ala37Val Uncertain significance ★ ⚠ same condition
HFE p.Arg180Met Uncertain significance ★ 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-trp74ser (accessed [today's date]).

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