EMC2

Chr 8

ER membrane protein complex subunit 2

Also known as: KIAA0103, TTC35

NCBI Gene: 9694 ENSG00000104412 UniProt: Q15006 OMIM: 607722

EMC2 encodes a component of the endoplasmic reticulum membrane protein complex (EMC) that facilitates the insertion of newly synthesized membrane proteins into ER membranes, particularly those with weakly hydrophobic transmembrane domains. Mutations cause a severe neurodevelopmental disorder with early infantile onset characterized by intellectual disability, developmental delay, seizures, and brain malformations. This condition follows an autosomal recessive inheritance pattern.

OMIM ResearchSummary from RefSeq, UniProt

Contributes to membrane insertase activity. Involved in protein insertion into ER membrane by stop-transfer membrane-anchor sequence and tail-anchored membrane protein insertion into ER membrane. Located in endoplasmic reticulum membrane. Is extrinsic component of endoplasmic reticulum membrane. Part of EMC complex. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

DNmechanismLOEUF 0.67

Clinical Summary— EMC2

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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

24 VUS of 47 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?

0.67LOEUF

pLI 0.003

Z-score 2.71

OE 0.37 (0.22–0.67)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.62Z-score

OE missense 0.86 (0.74–0.99)

128 obs / 149.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.37 (0.22–0.67)

0≤0.351.4

Missense OE?0.86 (0.74–0.99)

0≤0.61.4

Synonymous OE?1.07

0≤1.21.6

LoF obs/exp: 8 / 21.6Missense obs/exp: 128 / 149.3Syn Z: -0.41

This gene — mechanism propensity

0.7033th %ile

GOF

0.6247th %ile

LOF

0.2678th %ile

The highest-scoring mechanism for this gene is dominant-negative.

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

47 submitted variants in ClinVar

ClinVar

Classification Summary

VUS24

VUS

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Total
Pathogenic	0	0
Likely Pathogenic	0	0
VUS	24	24
Likely Benign	0	0
Benign	0	0
Total	24	24

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

View in ClinVar →

37 pathogenic / likely-pathogenic (of 40) ClinVar copy-number / structural variants overlap EMC2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →