Is HFE p.Leu46= (c.136T>C) pathogenic?

HFE p.Leu46= (c.136T>C) is classified Likely benign in HFE (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-31). Very rare (popmax 8.47e-05%, nfe); Associated with hereditary hemochromatosis.

What condition is associated with HFE p.Leu46= (c.136T>C)?

HFE p.Leu46= (c.136T>C) is associated with hereditary hemochromatosis (ClinVar).

How common is HFE p.Leu46= (c.136T>C) in the general population?

HFE p.Leu46= (c.136T>C) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

HFE p.Leu46=

c.136T>C · rs1205608152 · VCV1559454

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Conditions

hereditary hemochromatosis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP -0.2
Overall
CADD	6.405	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,032 alleles

Overall 0.000137% 2/1,461,880 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,510
European (non-Finnish)grpmax	8.47e-05%	1,180,032

Remaining individuals 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.Leu46=
Coding: c.136T>C
dbSNP: rs1205608152
Type: single nucleotide variant
Location: chr6:26090900 (GRCh38)

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

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-leu46 (accessed [today's date]).

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