Is HFE p.Phe58= (c.174C>T) pathogenic?

HFE p.Phe58= (c.174C>T) is classified Likely benign in HFE (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-16). Ultra-rare (popmax 0.0467%, afr); Associated with hereditary hemochromatosis.

What condition is associated with HFE p.Phe58= (c.174C>T)?

HFE p.Phe58= (c.174C>T) is associated with hereditary hemochromatosis (ClinVar).

How common is HFE p.Phe58= (c.174C>T) in the general population?

HFE p.Phe58= (c.174C>T) is ultra-rare (popmax 0.0467%, afr) (gnomAD).

HFE p.Phe58=

c.174C>T · rs147297176 · VCV1141885

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0467%, afr)

Conditions

hereditary hemochromatosis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -8.1
Overall
CADD	1.017	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0467% African / African-American · 35/75,006 alleles

Filtering AF 0.0345% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0302%

Overall 0.00304% 49/1,614,078 alleles · ultra-rare exomes 23/1,461,884 · genomes 26/152,194 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0467%	2,143
East Asian	0.00669%	14,959
Admixed American	0.00333%	30,005
Remaining individualsnot grpmax-eligible	0.0032%	31,254
South Asian	0.0022%	45,536
European (non-Finnish)	0.000424%	236,001

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.Phe58=
Coding: c.174C>T
MANE Select: NM_000410
dbSNP: rs147297176
Type: single nucleotide variant
Location: chr6:26090938 (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 58: a β-strand; the 'alpha-1' region

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 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
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-phe58 (accessed [today's date]).

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