DLG4

Chr 17AD

discs large MAGUK scaffold protein 4

Also known as: MRD62, PSD95, SAP-90, SAP90

NCBI Gene: 1742ENSG00000132535UniProt: P78352OMIM: 602887

The DLG4 protein heteromultimerizes with DLG2 to form postsynaptic scaffolds that cluster NMDA receptors, potassium channels, and associated signaling proteins at synapses. Loss-of-function mutations cause autosomal dominant intellectual developmental disorder. The high constraint scores (pLI 0.999, LOEUF 0.238) indicate this gene is highly intolerant to loss-of-function variants, consistent with the dominant inheritance pattern where haploinsufficiency disrupts synaptic function.

GeneReviewsOMIMResearchSummary from RefSeq, OMIM, UniProt, Mechanism
LOFmechanismADLOEUF 0.241 OMIM phenotype
Clinical Summary— DLG4
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Gene-Disease Validity (ClinGen)
complex neurodevelopmental disorder · ADDefinitive

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
106 unique Pathogenic / Likely Pathogenic· 131 VUS of 333 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 →
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GeneReview available — DLG4
Authoritative clinical overview · Recommended first read
Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
LoF Constraint
0.24LOEUF
pLI 1.000
Z-score 5.46
OE 0.11 (0.06–0.24)
Highly constrained

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

Missense Constraint
4.93Z-score
OE missense 0.36 (0.32–0.41)
174 obs / 477.3 exp
Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios
LoF OE0.11 (0.06–0.24)
0≤0.351.4
Missense OE0.36 (0.32–0.41)
0≤0.61.4
Synonymous OE0.93
0≤1.21.6
LoF obs/exp: 5 / 44.1Missense obs/exp: 174 / 477.3Syn Z: 0.82
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
strongDLG4-related intellectual disabilityLOFAD
DN
0.4685th %ile
GOF
0.6248th %ile
LOF
0.71top 10%

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

LOFprediction above median · 1 literature citation · 66% of P/LP variants are LoF · LOEUF 0.24

Literature Evidence

LOFIn a 23-year-old French man (patient 1) with autosomal dominant intellectual developmental disorder-62 (MRD62; 618793), Moutton et al. (2018) identified a de novo heterozygous 1-bp deletion (c.1843delG, NM_001365.3) in exon 19 of the DLG4 gene, resulting in a frameshift and premature termination (GlPMID:29460436

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

333 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic67
Likely Pathogenic39
VUS131
Likely Benign45
Benign17
Conflicting6
67
Pathogenic
39
Likely Pathogenic
131
VUS
45
Likely Benign
17
Benign
6
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
40
1
26
0
67
Likely Pathogenic
30
4
3
2
39
VUS
11
97
22
1
131
Likely Benign
0
5
13
27
45
Benign
0
3
9
5
17
Conflicting
—6
Total811107335305

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

View in ClinVar →

Protein Context — Lollipop Plot

DLG4 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

3D Protein StructureAlphaFold
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients