EMP2

Chr 16AR

epithelial membrane protein 2

Also known as: XMP

NCBI Gene: 2013 ENSG00000213853 UniProt: P54851 OMIM: 602334

The EMP2 protein is a tetraspan membrane protein that regulates cell membrane composition by controlling protein surface expression and modulating integrin function, focal adhesions, and angiogenesis. Mutations cause nephrotic syndrome type 10, a kidney disorder affecting glomerular filtration, with autosomal recessive inheritance. The gene shows low constraint against loss-of-function variants (LOEUF 1.88), consistent with recessive disease requiring biallelic mutations.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a tetraspan protein of the PMP22/EMP family. The encoded protein regulates cell membrane composition. It has been associated with various functions including endocytosis, cell signaling, cell proliferation, cell migration, cell adhesion, cell death, cholesterol homeostasis, urinary albumin excretion, and embryo implantation. It is known to negatively regulate caveolin-1, a scaffolding protein which is the main component of the caveolae plasma membrane invaginations found in most cell types. Through activation of PTK2 it positively regulates vascular endothelial growth factor A. It also modulates the function of specific integrin isomers in the plasma membrane. Up-regulation of this gene has been linked to cancer progression in multiple different tissues. Mutations in this gene have been associated with nephrotic syndrome type 10 (NPHS10). [provided by RefSeq, Mar 2015]

OMIM ResearchGenerating clinical summary…

MultiplemechanismARLOEUF 1.881 OMIM phenotype

Clinical Summary— EMP2

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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

3 unique Pathogenic / Likely Pathogenic· 43 VUS of 121 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.88LOEUF

pLI 0.000

Z-score -0.70

OE 1.29 (0.76–1.88)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.44Z-score

OE missense 1.12 (0.96–1.31)

118 obs / 105.3 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?1.29 (0.76–1.88)

0≤0.351.4

Missense OE?1.12 (0.96–1.31)

0≤0.61.4

Synonymous OE?1.03

0≤1.21.6

LoF obs/exp: 9 / 7.0Missense obs/exp: 118 / 105.3Syn Z: -0.14

This gene — mechanism propensity

0.6744th %ile

GOF

0.77top 25%

LOF

0.2485th %ile

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

GOFprediction above median

DNprediction 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

121 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1

Likely Pathogenic2

VUS43

Likely Benign41

Benign23

Conflicting1

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	1	0	0	1
Likely Pathogenic	2	0	0	0	2
VUS	2	40	1	0	43
Likely Benign	0	2	19	20	41
Benign	0	0	20	3	23
Conflicting	—				1
Total	4	43	40	23	111

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

View in ClinVar →

20 pathogenic / likely-pathogenic (of 40) ClinVar copy-number / structural variants overlap EMP2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →