Is HFE p.Gln283Pro (c.848A>C) pathogenic?

HFE p.Gln283Pro (c.848A>C) is classified Pathogenic/Likely pathogenic in HFE (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-06-11). AlphaMissense: likely pathogenic (0.7311); Very rare (popmax 0.000339%, nfe); Associated with hemochromatosis type 1.

What condition is associated with HFE p.Gln283Pro (c.848A>C)?

HFE p.Gln283Pro (c.848A>C) is associated with hemochromatosis type 1, hereditary hemochromatosis (ClinVar).

How common is HFE p.Gln283Pro (c.848A>C) in the general population?

HFE p.Gln283Pro (c.848A>C) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about HFE p.Gln283Pro (c.848A>C)?

AlphaMissense predicts likely pathogenic (score 0.7311) — an in-silico prediction, not a clinical call.

HFE p.Gln283Pro

c.848A>C · rs111033563 · VCV19

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.7311 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hemochromatosis type 1

Computational evidence

Protein change
AlphaMissense	0.7311	likely pathogenic ✓ concordant with ClinVar
REVEL	0.249	benign-leaning
SaProt	LLR -15.19	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	Δ0.21	donor loss, 1 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP -0.14
Regional constraint	o/e 0.93	unconstrained · MANE · 2,652 bp · p 0.31 · regional, not allelic
Overall
CADD	19.04	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

Grpmax group 0.000339% European (non-Finnish) · 4/1,180,016 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.00041% 6/1,461,856 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,254
European (non-Finnish)grpmax	0.000339%	295,004

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.Gln283Pro
Coding: c.848A>C
MANE Select: NM_000410
dbSNP: rs111033563
Type: single nucleotide variant
Location: chr6:26092916 (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 283: a UniProt-annotated variant site (in hfe1; destabilizing effect on the tertiary structure of the protein; prevents the normal interaction between hfe and b2m and between hfe and tfrc; decreases the capacity of hfe to reduce transferrin-mediated iron uptake); the ig-like c1-type domain; the 'alpha-3' region; a β-strand

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 p.Gln283= Likely benign ★ 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.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-gln283pro (accessed [today's date]).

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