DLG3

Chr XXLR

discs large MAGUK scaffold protein 3

Also known as: MRX, MRX90, NEDLG, PPP1R82, SAP102, XLID90, XLMR

NCBI Gene: 1741 ENSG00000082458 UniProt: Q13368 OMIM: 300189

This protein is required for learning through its role in synaptic plasticity following NMDA receptor signaling and clusters NMDA receptors at excitatory synapses. Mutations cause X-linked intellectual developmental disorder. The gene is highly constrained against loss-of-function variants (pLI ~1.0, LOEUF 0.09) and follows X-linked recessive inheritance.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a member of the membrane-associated guanylate kinase protein family. The encoded protein may play a role in clustering of NMDA receptors at excitatory synapses. It may also negatively regulate cell proliferation through interaction with the C-terminal region of the adenomatosis polyposis coli tumor suppressor protein. Mutations in this gene have been associated with X-linked cognitive disability. Alternatively spliced transcript variants have been described. [provided by RefSeq, Oct 2009]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Intellectual developmental disorder, X-linked 90MIM #300850

XLR

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · non-syndromic X-linked intellectual disability · XL · ClinGen 2018

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.09

LOEUF· LoF intol.

LOF

Mechanism· G2P

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — X-linked: males carry a single copy

LoF Constraint?

0.09LOEUF

pLI 1.000

Z-score 5.35

OE 0.00 (0.00–0.09)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?

2.88Z-score

OE missense 0.56 (0.49–0.63)

186 obs / 333.9 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.09)

0≤0.351.4

Missense OE?0.56 (0.49–0.63)

0≤0.61.4

Synonymous OE?0.92

0≤1.21.6

LoF obs/exp: 0 / 33.3Missense obs/exp: 186 / 333.9Syn Z: 0.70

Background carrier burden — how many people carry a rare variant somewhere in DLG3?

gnomAD v4 · ~732k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 210

575 rare PASS variants

Rare truncating (LoF)

1 in 9,000

27 rare PASS variants

Rare synonymous (reference)

1 in 140

320 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for DLG3. 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)	~561k	1 in 240	1 in 11,000
South Asian	~36k	1 in 120	1 in 6,700
Remaining (unassigned)	~31k	1 in 230	≈ 1 in 15,000
European (Finnish)	~27k	1 in 480	≈ 1 in 5,500
Admixed American	~23k	1 in 190	≈ 1 in 10,000
African / African American	~21k	1 in 160	≈ 1 in 6,500
East Asian	~20k	1 in 120	≈ 1 in 19,000
Ashkenazi Jewish	~13k	1 in 240	none seen
Middle Eastern	~2,758	1 in 220	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.