Is HJV p.Arg288Pro (c.863G>C) pathogenic?

HJV p.Arg288Pro (c.863G>C) is classified Uncertain significance in HJV (ClinVar, Single submitter, 2 submitters; last evaluated 2025-10-10). AlphaMissense: likely pathogenic (0.9855); Absent from gnomAD v4.1; Associated with hemochromatosis type 2A.

What condition is associated with HJV p.Arg288Pro (c.863G>C)?

HJV p.Arg288Pro (c.863G>C) is associated with hemochromatosis type 2A (ClinVar).

How common is HJV p.Arg288Pro (c.863G>C) in the general population?

HJV p.Arg288Pro (c.863G>C) is absent from gnomAD v4.1 (gnomAD).

How is HJV or HAMP-related hemochromatosis inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about HJV p.Arg288Pro (c.863G>C)?

AlphaMissense predicts likely pathogenic (score 0.9855) — an in-silico prediction, not a clinical call.

HJV p.Arg288Pro

c.863G>C · VCV4069259

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9855 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt

Conditions

hemochromatosis type 2A

Computational evidence

Protein change
AlphaMissense	0.9855	likely pathogenic · top 5% in HJV
SaProt	LLR -17.89	damaging
⇒ AlphaMissense and SaProt both call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.9, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 2,151 bp · p 0.42 · regional, not allelic
Overall
CADD	28.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; SaProt is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: HJV
Protein: p.Arg288Pro
Coding: c.863G>C
MANE Select: NM_213653
Type: single nucleotide variant
Location: chr1:146018495 (GRCh38)
Gene constraint: LOEUF 1.148 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 82.87 · 2 PDB
Residue 288: a UniProt-annotated variant site (in hfe2a)

Full HJV gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hemochromatosis type 2A — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For HJV or HAMP-related hemochromatosis (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Childhood

Similar variants

HJV p.Arg288Trp Conflicting classifications of pathogenicity ★ ⚠ same residue
HJV p.Arg288Gln Uncertain significance ★★ ⚠ same residue
HJV p.Arg288Leu Uncertain significance ★ ⚠ same residue
HJV p.Arg257Ter Pathogenic/Likely pathogenic ★★ same condition
HJV p.Arg326Ter Pathogenic/Likely pathogenic ★★ same condition
HJV p.Arg385Ter Likely pathogenic ★★ same condition
HJV p.Arg63Ter Pathogenic/Likely pathogenic ★★ same condition
HJV p.Cys80Arg 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/hjv-p-arg288pro (accessed [today's date]).

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