IER3IP1

Chr 18AR

immediate early response 3 interacting protein 1

Also known as: HSPC039, MEDS, PRO2309

NCBI Gene: 51124ENSG00000134049UniProt: Q9Y5U9

This gene encodes a small protein that is localized to the endoplasmic reticulum (ER) and may play a role in the ER stress response by mediating cell differentiation and apoptosis. Transcription of this gene is regulated by tumor necrosis factor alpha and specificity protein 1 (Sp1). Mutations in this gene may play a role in microcephaly, epilepsy, and diabetes syndrome (MEDS), and a pseudogene of this gene is located on the long arm of chromosome 12. [provided by RefSeq, Dec 2011]

Primary Disease Associations & Inheritance

Microcephaly, epilepsy, and diabetes syndromeMIM #614231
AR
0
Active trials
0
Pathogenic / LP
0
ClinVar variants
5
Pubs (1 yr)
-0.4
Missense Z
1.41
LOEUF
Clinical Summary— IER3IP1
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.02) — loss-of-function variants are relatively tolerated in the population.

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint
1.41LOEUF
pLI 0.023
Z-score 0.95
OE 0.56 (0.25–1.41)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint
-0.39Z-score
OE missense 1.17 (0.93–1.48)
50 obs / 42.8 exp
Tolerant

Tolerant to missense variation

Observed / Expected Ratios
LoF OE0.56 (0.25–1.41)
0≤0.351.4
Missense OE1.17 (0.93–1.48)
0≤0.61.4
Synonymous OE1.37
0≤1.21.6
LoF obs/exp: 3 / 5.4Missense obs/exp: 50 / 42.8Syn Z: -1.23
DNGOF
DN
0.84top 10%
GOF
0.80top 10%
LOF
0.3358th %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

0 submitted variants in ClinVar

ClinVar

IER3IP1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

IER3IP1-related microcephaly with simplified gyral pattern, epilepsy, and neonatal diabetes

strong
ARUndeterminedDecreased Gene Product Level
Dev. Disorders
G2P ↗
missense variantframeshift variant NMD escaping

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Landmark / reviewRecent case evidence
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients