SCRIB

Chr 8

scribble planar cell polarity protein

Also known as: CRIB1, SCRB1, SCRIB1, Vartul, oSCRIB

NCBI Gene: 23513 ENSG00000180900 OMIM: 607733

The SCRIB protein functions as a scaffold protein involved in cell polarization processes and tumor suppression pathways, binding to multiple other proteins through its PDZ domain. Mutations cause autosomal dominant neural tube defects including spina bifida and anencephaly. This gene is highly constrained against loss-of-function variants (pLI = 0.93, LOEUF = 0.31), indicating that complete loss of function is likely not tolerated.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a protein that was identified as being similar to the Drosophila scribble protein. The mammalian protein is involved in tumor suppression pathways. As a scaffold protein involved in cell polarization processes, this protein binds to many other proteins. The encoded protein binds to papillomavirus E6 protein via its PDZ domain and the C-terminus of E6. Two alternatively spliced transcript variants that encode different protein isoforms have been found for this gene. [provided by RefSeq, Nov 2011]

OMIM ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.31

Clinical Summary— SCRIB

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.93). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

1 unique Pathogenic / Likely Pathogenic· 349 VUS of 517 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?

0.31LOEUF

pLI 0.929

Z-score 6.21

OE 0.20 (0.13–0.31)

Highly constrained

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

Missense Constraint?

0.38Z-score

OE missense 0.97 (0.92–1.02)

982 obs / 1016.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.20 (0.13–0.31)

0≤0.351.4

Missense OE?0.97 (0.92–1.02)

0≤0.61.4

Synonymous OE?1.36

0≤1.21.6

LoF obs/exp: 14 / 70.2Missense obs/exp: 982 / 1016.2Syn Z: -6.03

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

limitedSCRIB-related 8q24.3 deletion-like syndromeLOFAD

This gene — mechanism propensity

0.5280th %ile

GOF

0.74top 25%

LOF

0.59top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFLOEUF 0.31

GOFprediction 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. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

517 submitted variants in ClinVar

ClinVar

Classification Summary

Likely Pathogenic1

VUS349

Likely Benign63

Benign22

Likely Pathogenic

349

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	1	0	0	0	1
VUS	1	347	1	0	349
Likely Benign	0	15	21	27	63
Benign	0	8	2	12	22
Total	2	370	24	39	435

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

View in ClinVar →

64 pathogenic / likely-pathogenic (of 70) ClinVar copy-number / structural variants overlap SCRIB — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →