PHLDB1

Chr 11AR

pleckstrin homology like domain family B member 1

Also known as: LL5A, LL5alpha, OI23

NCBI Gene: 23187 ENSG00000019144 UniProt: Q86UU1 OMIM: 612834

The PHLDB1 protein regulates embryonic development, epithelial to mesenchymal transition, and microtubule cytoskeleton organization. Mutations cause osteogenesis imperfecta type XXIII with autosomal recessive inheritance. The gene is highly constrained against loss-of-function variants (LOEUF 0.372), suggesting that complete loss of protein function is likely pathogenic.

OMIM ResearchSummary from RefSeq, OMIM

Involved in basement membrane organization. Located in basal cortex. Implicated in osteogenesis imperfecta. [provided by Alliance of Genome Resources, Jun 2026]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Osteogenesis imperfecta, type XXIIIMIM #620639

Clinical highlights

Gene–disease validity

Not independently assessedOMIM lists Osteogenesis imperfecta, type XXIII; no ClinGen or GenCC tier

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

0.37

LOEUF

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.37LOEUF

pLI 0.107

Z-score 5.53

OE 0.24 (0.16–0.37)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.47Z-score

OE missense 0.86 (0.81–0.91)

732 obs / 853.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.24 (0.16–0.37)

0≤0.351.4

Missense OE?0.86 (0.81–0.91)

0≤0.61.4

Synonymous OE?0.95

0≤1.21.6

LoF obs/exp: 15 / 62.0Missense obs/exp: 732 / 853.2Syn Z: 0.73

Background carrier burden — how many people carry a rare variant somewhere in PHLDB1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 31

1,792 rare PASS variants

Rare truncating (LoF)

1 in 1,200

191 rare PASS variants

Rare synonymous (reference)

1 in 58

756 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for PHLDB1. 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 38	1 in 1,300
South Asian	~43k	1 in 23	1 in 810
Remaining (unassigned)	~30k	1 in 29	1 in 2,200
European (Finnish)	~27k	1 in 99	1 in 1,500
Admixed American	~22k	1 in 30	1 in 1,500
African / African American	~21k	1 in 28	1 in 730
East Asian	~20k	1 in 35	1 in 520
Ashkenazi Jewish	~13k	1 in 87	≈ 1 in 6,100
Middle Eastern	~2,884	1 in 26	none seen

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): 17 of 22 coding exons well covered in gnomAD exomes; exons 2, 7, 20, 21, 22 marginal. Genomes: all 22.? see exons ↓