Is HFE p.Arg71Ter (c.211C>T) pathogenic?

HFE p.Arg71Ter (c.211C>T) is classified Pathogenic/Likely pathogenic in HFE (ClinVar, Multiple submitters, 4 submitters; last evaluated 2023-02-08). Ultra-rare (popmax 0.0134%, eas); Associated with hemochromatosis type 1.

What condition is associated with HFE p.Arg71Ter (c.211C>T)?

HFE p.Arg71Ter (c.211C>T) is associated with hemochromatosis type 1, hereditary hemochromatosis (ClinVar).

How common is HFE p.Arg71Ter (c.211C>T) in the general population?

HFE p.Arg71Ter (c.211C>T) is ultra-rare (popmax 0.0134%, eas) (gnomAD).

HFE p.Arg71Ter

c.211C>T · rs759524388 · VCV1073981

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0134%, eas)

Conditions

hemochromatosis type 1

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-escape possible for C-terminal truncations
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 0.21	phastCons 0.003
Overall
CADD	33.0	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 0.0134% East Asian · 6/44,892 alleles

Filtering AF 0.00579% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00394%

Overall 0.000929% 15/1,614,030 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0134%	7,482
Remaining individualsnot grpmax-eligible	0.0016%	62,484
European (non-Finnish)	0.000678%	147,505

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.Arg71Ter
Coding: c.211C>T
MANE Select: NM_000410
dbSNP: rs759524388
Type: single nucleotide variant
Location: chr6:26090975 (GRCh38)

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

Disease context

hemochromatosis type 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary hemochromatosis

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-arg71ter (accessed [today's date]).

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