HEG1

Chr 3

heart development protein with EGF like domains 1

Also known as: HEG, MST112, MSTP112

NCBI Gene: 57493 ENSG00000173706 UniProt: Q9ULI3 OMIM: 614182

The protein is a receptor component of the CCM signaling pathway that regulates heart and vessel formation and integrity through calcium ion binding and stabilization of endothelial cell junctions. Mutations cause cerebral cavernous malformation, which follows autosomal recessive inheritance and primarily affects the cerebrovascular system. The gene shows moderate constraint against loss-of-function variants (LOEUF 0.573).

OMIM ResearchSummary from RefSeq, UniProt

Predicted to enable calcium ion binding activity. Involved in several processes, including negative regulation of Rho protein signal transduction; negative regulation of membrane permeability; and obsolete negative regulation of Rho-dependent protein serine/threonine kinase activity. Located in cell-cell junction. [provided by Alliance of Genome Resources, Jun 2026]

OMIM ResearchGenerating clinical summary…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.57

LOEUF

Multiple*

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.57LOEUF

pLI 0.000

Z-score 4.05

OE 0.40 (0.28–0.57)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

0.47Z-score

OE missense 0.95 (0.89–1.01)

643 obs / 677.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.40 (0.28–0.57)

0≤0.351.4

Missense OE?0.95 (0.89–1.01)

0≤0.61.4

Synonymous OE?0.91

0≤1.21.6

LoF obs/exp: 21 / 52.7Missense obs/exp: 643 / 677.7Syn Z: 1.10

Background carrier burden — how many people carry a rare variant somewhere in HEG1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 28

1,764 rare PASS variants

Rare truncating (LoF)

1 in 510

137 rare PASS variants

Rare synonymous (reference)

1 in 52

762 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for HEG1. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 39	1 in 1,700
South Asian	~43k	1 in 25	1 in 3,000
Remaining (unassigned)	~30k	1 in 21	1 in 420
European (Finnish)	~27k	1 in 99	1 in 320
Admixed American	~22k	1 in 29	1 in 200
African / African American	~21k	1 in 30	1 in 320
East Asian	~20k	1 in 34	1 in 960
Ashkenazi Jewish	~13k	1 in 78	1 in 510
Middle Eastern	~2,884	1 in 27	≈ 1 in 700

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 14 of 17 coding exons well covered in gnomAD exomes; exons 1, 7, 9 marginal. Genomes: all 17.? see exons ↓