EHD2

Chr 19

EH domain containing 2

Also known as: PAST2

NCBI Gene: 30846 ENSG00000024422 UniProt: Q9NZN4 OMIM: 605890

The protein functions as an ATP- and membrane-binding protein that controls membrane reorganization and trafficking between the plasma membrane and endosomes, and is required for skeletal muscle myoblast fusion. Biallelic mutations cause autosomal recessive developmental and epileptic encephalopathy with movement abnormalities. The gene shows moderate constraint against loss-of-function variants (LOEUF 0.538), and the condition typically presents in early infancy with seizures and developmental delays.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a member of the EH domain-containing protein family. These proteins are characterized by a C-terminal EF-hand domain, a nucleotide-binding consensus site at the N terminus and a bipartite nuclear localization signal. The encoded protein interacts with the actin cytoskeleton through an N-terminal domain and also binds to an EH domain-binding protein through the C-terminal EH domain. This interaction appears to connect clathrin-dependent endocytosis to actin, suggesting that this gene product participates in the endocytic pathway. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.54

Clinical Summary— EHD2

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.23) despite low pLI — interpret in context.

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ClinVar Variants

84 VUS of 93 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.54LOEUF

pLI 0.308

Z-score 2.92

OE 0.23 (0.12–0.54)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.88Z-score

OE missense 0.73 (0.66–0.80)

269 obs / 371.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.23 (0.12–0.54)

0≤0.351.4

Missense OE?0.73 (0.66–0.80)

0≤0.61.4

Synonymous OE?0.95

0≤1.21.6

LoF obs/exp: 4 / 17.0Missense obs/exp: 269 / 371.0Syn Z: 0.50

This gene — mechanism propensity

0.6744th %ile

GOF

0.6639th %ile

LOF

0.3260th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median

GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

93 submitted variants in ClinVar

ClinVar

Classification Summary

VUS84

Likely Benign1

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	84	0	84
Likely Benign	0	1	1
Benign	0	0	0
Total	84	1	85

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

13 pathogenic / likely-pathogenic (of 22) ClinVar copy-number / structural variants overlap EHD2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →