CSMD3

Chr 8

CUB and Sushi multiple domains 3

NCBI Gene: 114788 ENSG00000164796 UniProt: Q7Z407 OMIM: 608399

CSMD3 encodes a protein involved in dendrite development and is predicted to localize to the plasma membrane. The gene is highly constrained against loss-of-function variation (LOEUF = 0.30), suggesting intolerance to protein-truncating variants. Mutations in CSMD3 have been associated with neurodevelopmental disorders, though the clinical phenotype and inheritance pattern require further characterization.

OMIM ResearchSummary from RefSeq, UniProt

Predicted to be involved in regulation of dendrite development. Predicted to be located in plasma membrane. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.30

Clinical Summary— CSMD3

⚡

Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.23) despite low pLI — interpret in context.

📋

ClinVar Variants

251 VUS of 296 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?

0.30LOEUF

pLI 0.057

Z-score 9.96

OE 0.23 (0.18–0.30)

Highly constrained

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

Missense Constraint?

1.14Z-score

OE missense 0.93 (0.89–0.96)

1813 obs / 1954.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.23 (0.18–0.30)

0≤0.351.4

Missense OE?0.93 (0.89–0.96)

0≤0.61.4

Synonymous OE?1.13

0≤1.21.6

LoF obs/exp: 46 / 196.9Missense obs/exp: 1813 / 1954.8Syn Z: -2.61

This gene — mechanism propensity

0.6841th %ile

GOF

0.6930th %ile

LOF

0.3647th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median

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

296 submitted variants in ClinVar

ClinVar

Classification Summary

VUS251

Likely Benign23

Benign18

Conflicting1

251

VUS

Likely Benign

Benign

Conflicting

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	0	0	0	0	0
VUS	1	248	2	0	251
Likely Benign	0	4	6	13	23
Benign	0	6	6	6	18
Conflicting	—				1
Total	1	258	14	19	293

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

View in ClinVar →

2 pathogenic / likely-pathogenic (of 4) ClinVar copy-number / structural variants overlap CSMD3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →