OCRL

Chr XXLR

OCRL inositol polyphosphate-5-phosphatase

Also known as: DENT2, Dent-2, LOCR, OCRL-1, OCRL1

NCBI Gene: 4952 ENSG00000122126 UniProt: Q01968 OMIM: 300535

This gene encodes an inositol polyphosphate 5-phosphatase that hydrolyzes phosphatidylinositol 4,5-bisphosphate and other phosphoinositides to regulate membrane trafficking, endosomal transport, and primary cilium formation. Mutations cause X-linked Lowe syndrome (oculocerebrorenal syndrome) and Dent disease 2, affecting the eyes, kidneys, and nervous system. The gene is highly constrained against loss-of-function variants (pLI 1.0, LOEUF 0.155) and follows X-linked recessive inheritance.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes an inositol polyphosphate 5-phosphatase. This protein is involved in regulating membrane trafficking and is located in numerous subcellular locations including the trans-Golgi network, clathrin-coated vesicles and, endosomes and the plasma membrane. This protein may also play a role in primary cilium formation. Mutations in this gene cause oculocerebrorenal syndrome of Lowe and also Dent disease. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

OMIM ResearchGenerating clinical summary…

LOFmechanismXLRLOEUF 0.153 OMIM phenotypes

Clinical Summary— OCRL

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Gene-Disease Validity (ClinGen)

oculocerebrorenal syndrome · XLDefinitive

Definitive — sufficient evidence for diagnostic panels

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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.

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ClinVar Variants

41 unique Pathogenic / Likely Pathogenic· 84 VUS of 280 total submissions

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Clinical Trials

2 active or recruiting trials — potential therapeutic options may be available

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?

0.15LOEUF

pLI 1.000

Z-score 5.62

OE 0.05 (0.02–0.15)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

2.96Z-score

OE missense 0.55 (0.49–0.62)

194 obs / 350.0 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.05 (0.02–0.15)

0≤0.351.4

Missense OE?0.55 (0.49–0.62)

0≤0.61.4

Synonymous OE?0.94

0≤1.21.6

LoF obs/exp: 2 / 40.7Missense obs/exp: 194 / 350.0Syn Z: 0.49

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveOCRL-related Dent DiseaseOTHERXLR

definitiveOCRL-related Lowe oculocerebrorenal syndromeLOFXLR

This gene — mechanism propensity

0.2798th %ile

GOF

0.3689th %ile

LOF

0.70top 10%

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

LOFprediction above median · 76% of P/LP variants are LoF · LOEUF 0.15 · ClinGen HI: Sufficient evidence for dosage pathogenicity

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

280 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic21

Likely Pathogenic20

VUS84

Likely Benign96

Benign6

Conflicting9

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	17	1	3	0	21
Likely Pathogenic	14	5	1	0	20
VUS	0	70	13	1	84
Likely Benign	0	12	40	44	96
Benign	0	0	2	4	6
Conflicting	—				9
Total	31	88	59	49	236

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

View in ClinVar →

15 pathogenic / likely-pathogenic (of 20) ClinVar copy-number / structural variants overlap OCRL — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →