HFE

Chr 6AR

homeostatic iron regulator

Also known as: HFE1, HH, HLA-H, MVCD7, TFQTL2

NCBI Gene: 3077 ENSG00000010704 UniProt: Q30201

The protein encoded by this gene is a membrane protein that is similar to MHC class I-type proteins and associates with beta2-microglobulin (beta2M). It is thought that this protein functions to regulate iron absorption by regulating the interaction of the transferrin receptor with transferrin. The iron storage disorder, hereditary haemochromatosis, is a recessive genetic disorder that results from defects in this gene. [provided by RefSeq, May 2022]

Primary Disease Associations & Inheritance

Hemochromatosis, type 1MIM #235200

UniProtHemochromatosis 1

349

ClinVar variants

Pathogenic / LP

0.00

pLI score

Active trials

Clinical Summary— HFE

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Gene-Disease Validity (ClinGen)

hemochromatosis type 1 · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

52 Pathogenic / Likely Pathogenic· 132 VUS of 349 total submissions

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Clinical Trials

12 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.

1.19LOEUF

pLI 0.000

Z-score 0.96

OE 0.76 (0.50–1.19)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.

0.63Z-score

OE missense 0.87 (0.77–0.99)

165 obs / 189.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.

LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.76 (0.50–1.19)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.87 (0.77–0.99)

0≤0.61.4

Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.89

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	10	1	21	0	32
Likely Pathogenic	13	3	4	0	20
VUS	5	88	38	1	132
Likely Benign	0	1	43	96	140
Benign	0	0	9	1	10
Conflicting	—				15
Total	28	93	115	98	349

HFE

Primary Disease Associations & Inheritance

Population Genetics & Constraint

ClinVar Variant Classifications

Classification Summary

Curated Variants Distribution

Protein Context — Lollipop Plot

DECIPHER · Gene2Phenotype

Gene2Phenotype Curations

OMIM — Genotype-Phenotype Relationships

Gene Overview

ClinGen Curation

Disease Associations

External Resources

Variant Interpretation

Population Databases

Gene Resources