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…

Clinical highlights

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

0.30

LOEUF· LoF intol.

Multiple*

Mechanism· predicted

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

Background carrier burden — how many people carry a rare variant somewhere in CSMD3?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 17

4,655 rare PASS variants

Rare truncating (LoF)

1 in 780

351 rare PASS variants

Rare synonymous (reference)

1 in 27

1,788 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for CSMD3. 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 24	1 in 780
South Asian	~43k	1 in 15	1 in 1,200
Remaining (unassigned)	~30k	1 in 15	1 in 2,100
European (Finnish)	~27k	1 in 42	1 in 660
Admixed American	~22k	1 in 17	1 in 680
African / African American	~21k	1 in 16	1 in 680
East Asian	~20k	1 in 16	1 in 880
Ashkenazi Jewish	~13k	1 in 81	1 in 1,300
Middle Eastern	~2,884	1 in 17	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): 47 of 71 coding exons well covered in gnomAD exomes; exons 3, 8, 9, 12, 13 and 19 more marginal. Genomes: all 71.? see exons ↓