Is DLG4 p.Ser654Phe (c.1961C>T) pathogenic?

DLG4 p.Ser654Phe (c.1961C>T) is classified Uncertain significance in DLG4 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-02-19). AlphaMissense: likely pathogenic (0.7855); Very rare (popmax 0.00108%, nfe); Associated with DLG4-Related Synaptopathy.

What condition is associated with DLG4 p.Ser654Phe (c.1961C>T)?

DLG4 p.Ser654Phe (c.1961C>T) is associated with DLG4-Related Synaptopathy (ClinVar).

How common is DLG4 p.Ser654Phe (c.1961C>T) in the general population?

DLG4 p.Ser654Phe (c.1961C>T) is very rare (popmax 0.00108%, nfe) (gnomAD).

What do computational predictors say about DLG4 p.Ser654Phe (c.1961C>T)?

AlphaMissense predicts likely pathogenic (score 0.7855) — an in-silico prediction, not a clinical call.

DLG4 p.Ser654Phe

c.1961C>T · rs752934560 · VCV1199223

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7855 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00108%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

DLG4-Related Synaptopathy

Computational evidence

Protein change
AlphaMissense	0.7855	likely pathogenic
REVEL	0.517	indeterminate
SaProt	LLR -14.88	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.4, phastCons 1
Regional constraint	o/e 0.58	unconstrained · MANE · 13 kb · p 1.2e-30 · regional, not allelic
Overall
CADD	29.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00108% European (non-Finnish) · 12/1,115,248 alleles

Filtering AF 0.000574% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000453%

Overall 0.0009% 12/1,333,138 alleles · very rare

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.Ser654Phe
Coding: c.1961C>T
MANE Select: NM_001321075
dbSNP: rs752934560
Type: single nucleotide variant
Location: chr17:7191908 (GRCh38)
Gene constraint: LOEUF 0.151 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 78.00 · 24 PDB
Residue 654: a modified residue (phosphoserine); a UniProt-annotated variant site (in mrd62); the guanylate kinase-like domain

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

Disease context

DLG4-Related Synaptopathy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

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
DLG4 c.1693+1G>A Pathogenic/Likely pathogenic ★★ same type
DLG4 c.1866+2T>C Pathogenic/Likely pathogenic ★★ same type
DLG4 c.210+1G>T Likely pathogenic ★★ same type
DLG4 c.211-2A>G 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-ser654phe (accessed [today's date]).

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