PLEKHA5

Chr 12

pleckstrin homology domain containing A5

Also known as: PEPP-2, PEPP2

NCBI Gene: 54477ENSG00000052126UniProt: Q9HAU0

The PLEKHA5 protein binds phosphatidylinositol phosphates and is involved in reproductive system development, with subcellular localization to the cytosol and nucleoplasm. This gene is extremely intolerant to loss-of-function variants (pLI ~1.0, LOEUF 0.098), suggesting that mutations likely cause severe developmental disorders, though specific associated phenotypes have not yet been definitively established in humans. The inheritance pattern for PLEKHA5-related conditions remains to be determined as clinical cases are characterized.

Summary from RefSeq
Research Assistant →
0
Active trials
3
Pubs (1 yr)
42
P/LP submissions
2%
P/LP missense
0.10
LOEUF· LoF intol.
LOF
Mechanism· predicted
Clinical Summary— PLEKHA5
⚡
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
42 unique Pathogenic / Likely Pathogenic· 132 VUS of 235 total submissions
Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint
0.10LOEUF
pLI 1.000
Z-score 7.93
OE 0.04 (0.02–0.10)
Highly constrained

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

Missense Constraint
1.24Z-score
OE missense 0.87 (0.81–0.93)
580 obs / 670.4 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.04 (0.02–0.10)
0≤0.351.4
Missense OE0.87 (0.81–0.93)
0≤0.61.4
Synonymous OE0.89
0≤1.21.6
LoF obs/exp: 3 / 79.0Missense obs/exp: 580 / 670.4Syn Z: 1.33
DN
0.4289th %ile
GOF
0.5268th %ile
LOF
0.78top 5%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · LOEUF 0.10

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

235 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic39
Likely Pathogenic3
VUS132
Likely Benign20
Benign7
39
Pathogenic
3
Likely Pathogenic
132
VUS
20
Likely Benign
7
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
39
0
39
Likely Pathogenic
0
1
2
0
3
VUS
0
130
2
0
132
Likely Benign
0
7
2
11
20
Benign
0
4
1
2
7
Total01424613201

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

View in ClinVar →

Protein Context — Lollipop Plot

PLEKHA5 · protein map & ClinVar variants

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

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
TNFα activation of the PLEKHA5-FCRLA axis disturbs lipid metabolism, leading to the progression of cutaneous malignant melanoma.
Yan K et al.·Lipids Health Dis
2025Open Access
Single-cell transcriptomics and functional validation revealed PLEKHA5-L as a promoter of growth and migration in brain metastatic melanoma cells.
Tang X et al.·Front Oncol
2025Open AccessFunctional
PLEKHA5, PLEKHA6, and PLEKHA7 bind to PDZD11 to target the Menkes ATPase ATP7A to the cell periphery and regulate copper homeostasis.
Sluysmans S et al.·Mol Biol Cell
2021Open Access
WW, PH and C-Terminal Domains Cooperate to Direct the Subcellular Localizations of PLEKHA5, PLEKHA6 and PLEKHA7.
Sluysmans S et al.·Front Cell Dev Biol
2021Open Access
PLEKHA5 regulates the survival and peritoneal dissemination of diffuse-type gastric carcinoma cells with Met gene amplification.
Nagamura Y et al.·Oncogenesis
2021Open Access
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