Is CASK p.Arg254His (c.761G>A) pathogenic?

CASK p.Arg254His (c.761G>A) is classified Conflicting classifications of pathogenicity in CASK (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-12-21). AlphaMissense: likely benign (0.2138); Very rare (popmax 0.000337%, nfe); Associated with Intellectual disability, CASK-related, X-linked.

What condition is associated with CASK p.Arg254His (c.761G>A)?

CASK p.Arg254His (c.761G>A) is associated with Intellectual disability, CASK-related, X-linked, FG syndrome 4 (ClinVar).

How common is CASK p.Arg254His (c.761G>A) in the general population?

CASK p.Arg254His (c.761G>A) is very rare (popmax 0.000337%, nfe) (gnomAD).

What do computational predictors say about CASK p.Arg254His (c.761G>A)?

AlphaMissense predicts likely benign (score 0.2138) — an in-silico prediction, not a clinical call.

CASK p.Arg254His

c.761G>A · rs1569376084 · VCV587634

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2138 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000337%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Intellectual disability, CASK-related, X-linked

Computational evidence

Protein change
AlphaMissense	0.2138	likely benign
REVEL	0.367	indeterminate
SaProt	LLR -10.68	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.3, phastCons 1
Regional constraint	o/e 0.31	constrained · MANE · 286 kb · p 1e-25 · regional, not allelic
Overall
CADD	27.8	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 0.000337% European (non-Finnish) · 3/891,334 alleles

Filtering AF 9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.5e-05%

Overall 0.000274% 3/1,093,621 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.Arg254His
Coding: c.761G>A
MANE Select: NM_001367721
dbSNP: rs1569376084
Type: single nucleotide variant
Location: chrX:41660509 (GRCh38)
Structure: AlphaFold pLDDT 79.45 · 22 PDB
Residue 254: the protein kinase domain; a UniProt-annotated variant site (found in a patient with epilepsy and pontocerebellar hypoplasia; likely pathogenic); an α-helix

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

Disease context

Intellectual disability, CASK-related, X-linked — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: FG syndrome 4

Similar variants

CASK p.Arg254Cys Uncertain significance ★ ⚠ 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
CASK p.Glu102Gly 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-arg254his (accessed [today's date]).

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