PLEKHA5

Chr 12

pleckstrin homology domain containing A5

Also known as: PEPP-2, PEPP2

NCBI Gene: 54477 ENSG00000052126 UniProt: Q9HAU0 OMIM: 607770

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.

OMIM ResearchSummary from RefSeq

Predicted to enable phosphatidylinositol phosphate binding activity. Predicted to act upstream of or within reproductive system development. Located in cytosol. [provided by Alliance of Genome Resources, Jun 2026]

OMIM ResearchGenerating clinical summary…

Clinical highlights

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.10

LOEUF· LoF intol.

LOF

Mechanism· predicted

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 OE?0.04 (0.02–0.10)

0≤0.351.4

Missense OE?0.87 (0.81–0.93)

0≤0.61.4

Synonymous OE?0.89

0≤1.21.6

LoF obs/exp: 3 / 79.0Missense obs/exp: 580 / 670.4Syn Z: 1.33

Background carrier burden — how many people carry a rare variant somewhere in PLEKHA5?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 54

1,532 rare PASS variants

Rare truncating (LoF)

1 in 1,200

121 rare PASS variants

Rare synonymous (reference)

1 in 97

570 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for PLEKHA5. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 74	1 in 1,100
South Asian	~43k	1 in 37	1 in 1,300
Remaining (unassigned)	~30k	1 in 48	1 in 1,800
European (Finnish)	~27k	1 in 140	1 in 3,800
Admixed American	~22k	1 in 41	1 in 1,200
African / African American	~21k	1 in 48	1 in 880
East Asian	~20k	1 in 48	1 in 1,400
Ashkenazi Jewish	~13k	1 in 160	≈ 1 in 12,000
Middle Eastern	~2,884	1 in 60	≈ 1 in 2,900

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 8 of 31 coding exons well covered in gnomAD exomes; exons 17, 18 poorly covered; exons 2, 3, 4, 5, 6 and 16 more marginal. Genomes: all 31.? see exons ↓