Is DLG4 p.Arg474Gln (c.1421G>A) pathogenic?

DLG4 p.Arg474Gln (c.1421G>A) is classified Likely benign in DLG4 (ClinVar, Single submitter, 2 submitters; last evaluated 2025-03-01). AlphaMissense: likely benign (0.1252); Very rare (popmax 0.00992%, sas); Associated with intellectual disability.

What condition is associated with DLG4 p.Arg474Gln (c.1421G>A)?

DLG4 p.Arg474Gln (c.1421G>A) is associated with intellectual disability (ClinVar).

How common is DLG4 p.Arg474Gln (c.1421G>A) in the general population?

DLG4 p.Arg474Gln (c.1421G>A) is very rare (popmax 0.00992%, sas) (gnomAD).

What do computational predictors say about DLG4 p.Arg474Gln (c.1421G>A)?

AlphaMissense predicts likely benign (score 0.1252) — an in-silico prediction, not a clinical call.

DLG4 p.Arg474Gln

c.1421G>A · rs773473959 · VCV975682

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1252 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00992%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

intellectual disability

Computational evidence

Protein change
AlphaMissense	0.1252	likely benign
REVEL	0.626	indeterminate
SaProt	LLR -8.59	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.4, phastCons 1
Regional constraint	o/e 0.58	unconstrained · MANE · 13 kb · p 1.2e-30 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00992% South Asian · 9/90,730 alleles

Filtering AF 0.00515% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00377%

Overall 0.00205% 33/1,612,546 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0144%	6,934
South Asiangrpmax	0.00992%	10,081
East Asian	0.00223%	44,822
Admixed American	0.00167%	59,824
European (non-Finnish)	0.0011%	90,727

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: DLG4
Protein: p.Arg474Gln
Coding: c.1421G>A
MANE Select: NM_001321075
dbSNP: rs773473959
Type: single nucleotide variant
Location: chr17:7194376 (GRCh38)
Gene constraint: LOEUF 0.151 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 78.00 · 24 PDB
Residue 474: a UniProt-annotated variant site (in mrd62); the sh3 domain

Full DLG4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

intellectual disability — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

DLG4 p.Arg474Trp Uncertain significance ★ ⚠ same residue
DLG4 p.Trp471Ter Pathogenic ★★ same condition
DLG4 p.Arg455Cys Uncertain significance ★★ ⚠ same condition
DLG4 p.Arg309Gln Uncertain significance ★ ⚠ same condition
DLG4 c.1084-1G>T Pathogenic/Likely pathogenic ★★ same type
DLG4 c.1478+2T>C Pathogenic/Likely pathogenic ★★ same type
DLG4 c.1543+2T>C Pathogenic/Likely pathogenic ★★ same type
DLG4 c.1592-1G>A Pathogenic/Likely pathogenic ★★ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/dlg4-p-arg474gln (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown