Is HFE p.Phe251= (c.753C>T) pathogenic?

HFE p.Phe251= (c.753C>T) is classified Likely benign in HFE (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-29). Very rare (popmax 0.00347%, nfe); Associated with hereditary hemochromatosis.

What condition is associated with HFE p.Phe251= (c.753C>T)?

HFE p.Phe251= (c.753C>T) is associated with hereditary hemochromatosis (ClinVar).

How common is HFE p.Phe251= (c.753C>T) in the general population?

HFE p.Phe251= (c.753C>T) is very rare (popmax 0.00347%, nfe) (gnomAD).

HFE p.Phe251=

c.753C>T · rs150402693 · VCV700798

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00347%, nfe)

Conditions

hereditary hemochromatosis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -5.4
Overall
CADD	0.539	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00347% European (non-Finnish) · 41/1,180,036 alleles

Filtering AF 0.00259% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00233%

Overall 0.00322% 52/1,614,068 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00676%	14,803
Remaining individualsnot grpmax-eligible	0.0048%	20,829
European (non-Finnish)grpmax	0.00347%	28,781
Admixed American	0.00333%	30,007
African / African-American	0.00267%	37,460
East Asian	0.00223%	44,890
South Asian	0.0011%	91,082

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Phe251=
Coding: c.753C>T
MANE Select: NM_000410
dbSNP: rs150402693
Type: single nucleotide variant
Location: chr6:26092821 (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 251: a disulfide bond; the ig-like c1-type domain; the 'alpha-3' 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 p.Phe251Leu 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-phe251 (accessed [today's date]).

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