Is CASK p.Arg28Leu (c.83G>T) pathogenic?

CASK p.Arg28Leu (c.83G>T) is classified Pathogenic in CASK (ClinVar, No assertion criteria, 1 submitter; last evaluated 2009-02-01). AlphaMissense: likely pathogenic (0.9744); Absent from gnomAD v4.1; Associated with FG syndrome 4.

What condition is associated with CASK p.Arg28Leu (c.83G>T)?

CASK p.Arg28Leu (c.83G>T) is associated with FG syndrome 4 (ClinVar).

How common is CASK p.Arg28Leu (c.83G>T) in the general population?

CASK p.Arg28Leu (c.83G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CASK p.Arg28Leu (c.83G>T)?

AlphaMissense predicts likely pathogenic (score 0.9744) — an in-silico prediction, not a clinical call.

CASK p.Arg28Leu

c.83G>T · rs137852816 · VCV11532

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9744 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

FG syndrome 4

Computational evidence

Protein change
AlphaMissense	0.9744	likely pathogenic ✓ concordant with ClinVar
REVEL	0.477	indeterminate
SaProt	LLR -13.58	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 7.6	GERP 2.9, phastCons 1
Regional constraint	o/e 0.31	constrained · MANE · 286 kb · p 1e-25 · regional, not allelic
Overall
CADD	31.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CASK
Protein: p.Arg28Leu
Coding: c.83G>T
MANE Select: NM_001367721
dbSNP: rs137852816
Type: single nucleotide variant
Location: chrX:41853204 (GRCh38)
Structure: AlphaFold pLDDT 79.45 · 22 PDB
Residue 28: the protein kinase domain; a UniProt-annotated variant site (found in a patient with epilepsy and pontocerebellar hypoplasia; likely pathogenic); a UniProt-annotated variant site (in fgs4; does not reveal significant alterations induced by the mutation substitution; causes a partial skipping of exon 2 of the protein); a β-strand

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.Arg28Ter Pathogenic ★★ same residue
GPR82 p.Val28Ala Uncertain significance ★ same residue
CASK p.Arg28= 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.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-arg28leu (accessed [today's date]).

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