HIVEP2

Chr 6AD

HIVEP zinc finger 2

NCBI Gene: 3097ENSG00000010818UniProt: P31629

This protein specifically binds to the DNA sequence 5'-GGGACTTTCC-3' which is found in the enhancer elements of numerous viral promoters such as those of SV40, CMV, or HIV1. In addition, related sequences are found in the enhancer elements of a number of cellular promoters, including those of the class I MHC, interleukin-2 receptor, somatostatin receptor II, and interferon-beta genes. It may act in T-cell activation

Primary Disease Associations & Inheritance

Intellectual developmental disorder, autosomal dominant 43MIM #616977
AD
487
ClinVar variants
33
Pathogenic / LP
1.00
pLI score· haploinsufficient
1
Active trials
Clinical Summary— HIVEP2
⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
33 Pathogenic / Likely Pathogenic· 239 VUS of 487 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.08LOEUF
pLI 1.000
Z-score 8.02
OE 0.03 (0.01–0.08)
Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
1.83Z-score
OE missense 0.86 (0.82–0.90)
1129 obs / 1315.7 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.03 (0.01–0.08)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.86 (0.82–0.90)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.05
0≤1.21.6
LoF obs/exp: 2 / 78.8Missense obs/exp: 1129 / 1315.7Syn Z: -0.94

ClinVar Variant Classifications

487 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic22
Likely Pathogenic11
VUS239
Likely Benign149
Benign44
Conflicting22
22
Pathogenic
11
Likely Pathogenic
239
VUS
149
Likely Benign
44
Benign
22
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
10
0
12
0
22
Likely Pathogenic
9
0
2
0
11
VUS
1
230
8
0
239
Likely Benign
0
65
4
80
149
Benign
0
5
0
39
44
Conflicting
—22
Total2030026119487

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

View in ClinVar →

Protein Context — Lollipop Plot

HIVEP2 · protein map & ClinVar variants

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

Gene2Phenotype Curations

HIVEP2-related syndromic developmental delay with intellectual disability with or without microcephaly

definitive
ADLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Intellectual developmental disorder, autosomal dominant 43

MIM #616977

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — HIVEP2
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
De novo variants underlying monogenic syndromes with intellectual disability in a neurodevelopmental cohort from India.
Pande S et al.·Eur J Hum Genet
2024Cohort
Neurodevelopmental profile of HIVEP2-related disorder.
Mo A et al.·Dev Med Child Neurol
2022
METAP2 inhibits K48-linked ubiquitination of YTHDF2 to promote ovarian cancer progression.
Wu L et al.·Oncogene
2025
Identification of HIVEP2 as a dopaminergic transcription factor related to substance use disorders in rats and humans.
Zhao J et al.·Transl Psychiatry
2019
Mutations in HIVEP2 are associated with developmental delay, intellectual disability, and dysmorphic features.
Steinfeld H et al.·Neurogenetics
2016
Loss-of-function variants in HIVEP2 are a cause of intellectual disability.
Srivastava S et al.·Eur J Hum Genet
2016Case report
Expanding the phenotype of intellectual disability caused by HIVEP2 variants.
Goldsmith H et al.·Am J Med Genet A
2019Case report
HIVEP3 cooperates with ferroptosis gene signatures to confer adverse prognosis in acute myeloid leukemia.
Zhang X et al.·Cancer Med
2022
Genomic study of severe fetal anomalies and discovery of GREB1L mutations in renal agenesis.
Boissel S et al.·Genet Med
2018
Comprehensive genetic analysis confers high diagnostic yield in 16 Japanese patients with corpus callosum anomalies.
Miyamoto S et al.·J Hum Genet
2021Cohort
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
16P11.2 Deletion Syndrome16p11.2 Duplications1Q21.1 Deletion

Online Study of People Who Have Genetic Changes and Features of Autism: Simons Searchlight

RECRUITING
NCT01238250Simons SearchlightStarted 2010-10

External Resources

Links to major genomics databases and tools