PHLDB2

Chr 3

pleckstrin homology like domain family B member 2

Also known as: LL5b, LL5beta

NCBI Gene: 90102 ENSG00000144824 UniProt: Q86SQ0 OMIM: 610298

The PHLDB2 protein binds cadherins and is involved in assembling the postsynaptic apparatus, including acetylcholine receptor aggregation at the postsynaptic membrane. Mutations cause neurodevelopmental disorders with autosomal recessive inheritance. The gene shows moderate constraint against loss-of-function variants (LOEUF 0.591).

OMIM ResearchSummary from RefSeq, UniProt

Enables cadherin binding activity. Involved in several processes, including negative regulation of focal adhesion assembly; regulation of cytoskeleton organization; and regulation of embryonic development. Located in several cellular components, including basal cortex; cytoskeleton; and focal adhesion. [provided by Alliance of Genome Resources, Apr 2025]

OMIM ResearchGenerating clinical summary…

DNmechanismLOEUF 0.59

Clinical Summary— PHLDB2

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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

157 VUS of 188 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.59LOEUF

pLI 0.000

Z-score 4.01

OE 0.42 (0.30–0.59)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

0.38Z-score

OE missense 0.96 (0.90–1.02)

650 obs / 677.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.42 (0.30–0.59)

0≤0.351.4

Missense OE?0.96 (0.90–1.02)

0≤0.61.4

Synonymous OE?1.05

0≤1.21.6

LoF obs/exp: 23 / 55.1Missense obs/exp: 650 / 677.6Syn Z: -0.67

This gene — mechanism propensity

0.7228th %ile

GOF

0.6247th %ile

LOF

0.4234th %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

188 submitted variants in ClinVar

ClinVar

Classification Summary

VUS157

Likely Benign6

Benign8

157

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0
Likely Pathogenic	0	0	0	0
VUS	157	0	0	157
Likely Benign	5	1	0	6
Benign	5	1	2	8
Total	167	2	2	171

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

View in ClinVar →

16 pathogenic / likely-pathogenic (of 17) ClinVar copy-number / structural variants overlap PHLDB2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →