Is CASK p.Arg255His (c.764G>A) pathogenic?

CASK p.Arg255His (c.764G>A) is classified Conflicting classifications of pathogenicity in CASK (ClinVar, Conflicting submitters, 12 submitters; last evaluated 2025-08-27). AlphaMissense: likely pathogenic (0.7494); Absent from gnomAD v4.1; Associated with syndromic X-linked intellectual disability Najm type.

What condition is associated with CASK p.Arg255His (c.764G>A)?

CASK p.Arg255His (c.764G>A) is associated with syndromic X-linked intellectual disability Najm type, FG syndrome 4 (ClinVar).

How common is CASK p.Arg255His (c.764G>A) in the general population?

CASK p.Arg255His (c.764G>A) is absent from gnomAD v4.1 (gnomAD).

How is X-linked intellectual disability, Najm type inherited?

Typically X-linked dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about CASK p.Arg255His (c.764G>A)?

AlphaMissense predicts likely pathogenic (score 0.7494) — an in-silico prediction, not a clinical call.

CASK p.Arg255His

c.764G>A · rs587783369 · VCV158084

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 12 submitters

AlphaMissense

likely pathogenic

0.7494 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

syndromic X-linked intellectual disability Najm type

Computational evidence

Protein change
AlphaMissense	0.7494	likely pathogenic
REVEL	0.527	indeterminate
SaProt	LLR -11.11	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 1.3, phastCons 1
Regional constraint	o/e 0.31	constrained · MANE · 286 kb · p 1e-25 · regional, not allelic
Overall
CADD	28.9	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.Arg255His
Coding: c.764G>A
MANE Select: NM_001367721
dbSNP: rs587783369
Type: single nucleotide variant
Location: chrX:41660506 (GRCh38)
Structure: AlphaFold pLDDT 79.45 · 22 PDB
Residue 255: 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

syndromic X-linked intellectual disability Najm type — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: FG syndrome 4

For X-linked intellectual disability, Najm type (Orphanet):

Inheritance: X-linked dominant
Onset: Infancy, Neonatal

Similar variants

CASK p.Arg255Cys Pathogenic/Likely pathogenic ★★ same residue
CASK c.1015+1G>A Pathogenic ★★ same condition
CASK c.1315-1G>A Pathogenic/Likely pathogenic ★★ same condition
CASK c.2317+1G>A Pathogenic/Likely pathogenic ★★ same condition
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.Arg106Ter 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-arg255his (accessed [today's date]).

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