Is CASK p.Arg681Gln (c.2042G>A) pathogenic?

CASK p.Arg681Gln (c.2042G>A) is classified Uncertain significance in CASK (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-06-01). AlphaMissense: likely pathogenic (0.9783); Very rare (popmax 0.00299%, eas); Associated with FG syndrome 4.

What condition is associated with CASK p.Arg681Gln (c.2042G>A)?

CASK p.Arg681Gln (c.2042G>A) is associated with FG syndrome 4 (ClinVar).

How common is CASK p.Arg681Gln (c.2042G>A) in the general population?

CASK p.Arg681Gln (c.2042G>A) is very rare (popmax 0.00299%, eas) (gnomAD).

What do computational predictors say about CASK p.Arg681Gln (c.2042G>A)?

AlphaMissense predicts likely pathogenic (score 0.9783) — an in-silico prediction, not a clinical call.

CASK p.Arg681Gln

c.2042G>A · rs2064965930 · VCV1397133

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9783 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00299%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

FG syndrome 4

Computational evidence

Protein change
AlphaMissense	0.9783	likely pathogenic
REVEL	0.867	moderately pathogenic-leaning
SaProt	LLR -16.25	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.29	constrained · MANE · 11 kb · p 1.3e-08 · regional, not allelic
Overall
CADD	31.0	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 0.00299% East Asian · 1/33,432 alleles

Overall 0.0001% 1/995,761 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: CASK
Protein: p.Arg681Gln
Coding: c.2042G>A
MANE Select: NM_001367721
dbSNP: rs2064965930
Type: single nucleotide variant
Location: chrX:41542804 (GRCh38)
Structure: AlphaFold pLDDT 79.45 · 22 PDB
Residue 681: a UniProt-annotated variant site (found in a patient with epilepsy and pontocerebellar hypoplasia; likely pathogenic); the sh3 domain; the 'required for interaction with nrxn1 (via c-terminal tail)' region

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

Disease context

FG syndrome 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CASK p.Arg681Ter Pathogenic ★★ same residue
CASK p.Arg681= Likely benign ★ same residue
CASK c.2317+5G>A Pathogenic/Likely pathogenic ★★ same condition
CASK c.2521-2A>G Pathogenic/Likely pathogenic ★★ same condition
CASK c.59+2T>C Pathogenic/Likely pathogenic ★★ same condition
CASK p.Arg28Ter Pathogenic ★★ same condition
CASK p.Arg489Gln Pathogenic/Likely pathogenic ★★ same condition
CASK p.Arg613Ter Pathogenic/Likely pathogenic ★★ same condition

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/cask-p-arg681gln (accessed [today's date]).

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