Is HFE p.Arg161fs (c.480del) pathogenic?

HFE p.Arg161fs (c.480del) is classified Pathogenic in HFE (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-14). Very rare (popmax 0.00659%, sas); Associated with hereditary hemochromatosis.

What condition is associated with HFE p.Arg161fs (c.480del)?

HFE p.Arg161fs (c.480del) is associated with hereditary hemochromatosis (ClinVar).

How common is HFE p.Arg161fs (c.480del) in the general population?

HFE p.Arg161fs (c.480del) is very rare (popmax 0.00659%, sas) (gnomAD).

HFE p.Arg161fs

c.480del · rs777018511 · VCV1072713

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00659%, sas)

Conditions

hereditary hemochromatosis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 3 of 6
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.54	phastCons 0.99
Overall
CADD	19.89	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 0.00659% South Asian · 6/91,092 alleles

Filtering AF 0.00286% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00195%

Overall 0.00136% 22/1,614,016 alleles · very rare exomes 21/1,461,890 · genomes 1/152,126 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00659%	15,182
Remaining individualsnot grpmax-eligible	0.0016%	62,478
European (non-Finnish)	0.00127%	78,668

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.Arg161fs
Coding: c.480del
MANE Select: NM_000410
dbSNP: rs777018511
Type: Deletion
Location: chr6:26091451 (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 161: an α-helix; the 'alpha-2' region

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

Disease context

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

Similar variants

HFE p.His341fs Pathogenic ★★ same condition
HFE p.Leu183fs Pathogenic/Likely pathogenic ★★ same condition
HFE p.Trp94fs Pathogenic/Likely pathogenic ★★ same condition
HFE c.1006+19del Benign/Likely benign ★★ same condition
HFE p.Asn259fs Pathogenic ★ same condition
HFE p.Asp255fs Pathogenic ★ same condition
HFE p.Glu147fs Pathogenic ★ same condition
HFE p.Leu209fs 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-arg161fs (accessed [today's date]).

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