Is HAMP p.Phe63= (c.189C>T) pathogenic?

HAMP p.Phe63= (c.189C>T) is classified Conflicting classifications of pathogenicity in HAMP (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-10-08). Ultra-rare (popmax 0.0165%, mid); Associated with hemochromatosis type 2B.

What condition is associated with HAMP p.Phe63= (c.189C>T)?

HAMP p.Phe63= (c.189C>T) is associated with hemochromatosis type 2B, hereditary hemochromatosis (ClinVar).

How common is HAMP p.Phe63= (c.189C>T) in the general population?

HAMP p.Phe63= (c.189C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

How is HJV or HAMP-related hemochromatosis inherited?

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

HAMP p.Phe63=

c.189C>T · rs753934178 · VCV891879

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Conditions

hemochromatosis type 2B

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.054	GERP -2.3, phastCons 0.9
Overall
CADD	9.935	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,062 alleles

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

Overall 0.000372% 6/1,614,042 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
Remaining individualsnot grpmax-eligible	0.0016%	62,508
European (non-Finnish)	0.000339%	294,970

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: HAMP
Protein: p.Phe63=
Coding: c.189C>T
MANE Select: NM_021175
dbSNP: rs753934178
Type: single nucleotide variant
Location: chr19:35284976 (GRCh38)
Gene constraint: LOEUF 1.464 · pLI 0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.16 · 6 PDB

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

Also linked: hereditary hemochromatosis

For HJV or HAMP-related hemochromatosis (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Childhood

Similar variants

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.Arg59Gly Uncertain significance ★★ ⚠ same condition
HAMP p.Thr22Ile Uncertain significance ★★ ⚠ same condition
HAMP c.150+7G>C Likely benign ★★ same condition
HAMP p.Cys70= Likely benign ★★ same condition
HAMP p.Gly71Asp Benign/Likely benign ★★ 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-phe63 (accessed [today's date]).

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