Is HAMP p.Arg56Ter (c.166C>T) pathogenic?

HAMP p.Arg56Ter (c.166C>T) is classified Pathogenic in HAMP (ClinVar, No assertion criteria, 1 submitter; last evaluated 2003-01-01). Very rare (popmax 0.00223%, eas); Associated with hemochromatosis type 2B.

What condition is associated with HAMP p.Arg56Ter (c.166C>T)?

HAMP p.Arg56Ter (c.166C>T) is associated with hemochromatosis type 2B (ClinVar).

How common is HAMP p.Arg56Ter (c.166C>T) in the general population?

HAMP p.Arg56Ter (c.166C>T) is very rare (popmax 0.00223%, eas) (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.Arg56Ter

c.166C>T · rs104894695 · VCV4284

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

hemochromatosis type 2B

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (3 of 3) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.8	GERP 0.064, phastCons 0.005
Overall
CADD	36.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,876 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000479% 7/1,461,140 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,876
European (non-Finnish)	0.000509%	196,557

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.Arg56Ter
Coding: c.166C>T
MANE Select: NM_021175
dbSNP: rs104894695
Type: single nucleotide variant
Location: chr19:35284953 (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

For HJV or HAMP-related hemochromatosis (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Childhood

Similar variants

HAMP p.Arg56Gln Uncertain significance ★★ ⚠ same residue
HAMP c.-25G>A Pathogenic/Likely pathogenic ★★ same condition
HAMP p.Arg75Ter Likely pathogenic ★★ same condition
HAMP p.Arg59Gly Uncertain significance ★★ ⚠ same condition
HAMP p.Gly71Asp Benign/Likely benign ★★ same condition
HAMP p.His62Arg Likely pathogenic ★ ⚠ same condition
HAMP c.150+7G>A Conflicting classifications of pathogenicity ★ same condition
HAMP c.-1G>A Uncertain significance ★ 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-arg56ter (accessed [today's date]).

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