Is HFE p.Tyr342= (c.1026C>T) pathogenic?

HFE p.Tyr342= (c.1026C>T) is classified Conflicting classifications of pathogenicity in HFE (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-02-03). Low-frequency (popmax 1.52%, afr); Associated with hemochromatosis type 1.

What condition is associated with HFE p.Tyr342= (c.1026C>T)?

HFE p.Tyr342= (c.1026C>T) is associated with hemochromatosis type 1, hereditary hemochromatosis (ClinVar).

How common is HFE p.Tyr342= (c.1026C>T) in the general population?

HFE p.Tyr342= (c.1026C>T) is low-frequency (popmax 1.52%, afr) (gnomAD).

HFE p.Tyr342=

c.1026C>T · rs35201683 · VCV237780

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.52%, afr)

Conditions

hemochromatosis type 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.36 · evaluated, not missing
Pangolin	Δ0.25	loss · gain 0.00 · SpliceAI below 0.2 · independent
Constraint at this position
Conservation	phyloP -3.9	GERP -4.6
Overall
CADD	3.702	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.52% African / African-American · 1,139/75,022 alleles

Filtering AF 1.44% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.42%

Overall 0.0976% 1,575/1,613,918 alleles · low-frequency exomes 854/1,461,642 · genomes 721/152,276 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.52%	66
Middle Eastern	0.284%	352
Admixed American	0.227%	441
Remaining individualsnot grpmax-eligible	0.144%	694
South Asian	0.0264%	3,795
European (non-Finnish)	0.0141%	7,108
East Asian	0.00446%	22,444
Finnishnot grpmax-eligible	0.00156%	63,988

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.Tyr342=
Coding: c.1026C>T
MANE Select: NM_000410
dbSNP: rs35201683
Type: single nucleotide variant
Location: chr6:26094205 (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

hemochromatosis type 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary hemochromatosis

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-tyr342 (accessed [today's date]).

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