Is HAMP p.Arg59Pro (c.176G>C) pathogenic?

HAMP p.Arg59Pro (c.176G>C) is classified Pathogenic in HAMP (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-07-16). AlphaMissense: likely pathogenic (0.589); Absent from gnomAD v4.1; Associated with hemochromatosis type 2B.

What condition is associated with HAMP p.Arg59Pro (c.176G>C)?

HAMP p.Arg59Pro (c.176G>C) is associated with hemochromatosis type 2B (ClinVar).

How common is HAMP p.Arg59Pro (c.176G>C) in the general population?

HAMP p.Arg59Pro (c.176G>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 HAMP p.Arg59Pro (c.176G>C)?

AlphaMissense predicts likely pathogenic (score 0.589) — an in-silico prediction, not a clinical call.

HAMP p.Arg59Pro

c.176G>C · rs2066319871 · VCV917401

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.589 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hemochromatosis type 2B

Computational evidence

Protein change
AlphaMissense	0.589	likely pathogenic ✓ concordant with ClinVar
REVEL	0.667	pathogenic-leaning
SaProt	LLR -8.76	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.2	GERP 1.2, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 2,461 bp · p 0.93 · regional, not allelic
Overall
CADD	25.0	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

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: HAMP
Protein: p.Arg59Pro
Coding: c.176G>C
MANE Select: NM_021175
dbSNP: rs2066319871
Type: single nucleotide variant
Location: chr19:35284963 (GRCh38)
Gene constraint: LOEUF 1.464 · pLI 0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.16 · 6 PDB
Residue 59: a UniProt-annotated variant site (in hfe2b)

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

Disease context

hemochromatosis type 2B — 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

HAMP p.Arg59Gly Uncertain significance ★★ ⚠ same residue
HAMP p.Arg59Gln Uncertain significance ★ ⚠ same residue
HAMP p.Arg59Ter Uncertain significance ★ same residue
HAMP c.-25G>A Pathogenic/Likely pathogenic ★★ same condition
HAMP p.Arg75Ter Likely pathogenic ★★ same condition
HAMP p.Arg56Gln Uncertain significance ★★ ⚠ same condition
HAMP p.Gly71Asp Benign/Likely benign ★★ same condition
HAMP p.His62Arg 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/hamp-p-arg59pro (accessed [today's date]).

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