Is CASK p.Cys418Tyr (c.1253G>A) pathogenic?

CASK p.Cys418Tyr (c.1253G>A) is classified Uncertain significance in CASK (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-30). AlphaMissense: likely benign (0.2262); Absent from gnomAD v4.1; Associated with Intellectual disability, CASK-related, X-linked.

What condition is associated with CASK p.Cys418Tyr (c.1253G>A)?

CASK p.Cys418Tyr (c.1253G>A) is associated with Intellectual disability, CASK-related, X-linked (ClinVar).

How common is CASK p.Cys418Tyr (c.1253G>A) in the general population?

CASK p.Cys418Tyr (c.1253G>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CASK p.Cys418Tyr (c.1253G>A)?

AlphaMissense predicts likely benign (score 0.2262) — an in-silico prediction, not a clinical call.

CASK p.Cys418Tyr

c.1253G>A · rs2519844930 · VCV2995984

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2262 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,152,750)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Intellectual disability, CASK-related, X-linked

Computational evidence

Protein change
AlphaMissense	0.2262	likely benign
REVEL	0.339	indeterminate
SaProt	LLR -5.92	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 1.3, phastCons 1
Regional constraint	o/e 0.50	unconstrained · MANE · 77 kb · p 1.9e-13 · regional, not allelic
Overall
CADD	23.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

No allele count reported in gnomAD v4.1 (AN 1,152,750). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: CASK
Protein: p.Cys418Tyr
Coding: c.1253G>A
MANE Select: NM_001367721
dbSNP: rs2519844930
Type: single nucleotide variant
Location: chrX:41586968 (GRCh38)
Structure: AlphaFold pLDDT 79.45 · 22 PDB
Residue 418: a UniProt-annotated variant site (found in a patient with epilepsy and pontocerebellar hypoplasia; likely pathogenic); the l27 2 domain

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

Similar variants

CASK p.Arg489Gln Pathogenic/Likely pathogenic ★★ same condition
CASK p.Ala359Val Uncertain significance ★★ ⚠ same condition
CASK p.Ala833Thr Uncertain significance ★★ ⚠ same condition
CASK p.Arg130Cys Uncertain significance ★★ ⚠ same condition
CASK p.Arg572His Uncertain significance ★★ ⚠ same condition
CASK p.Arg61Trp Uncertain significance ★★ ⚠ same condition
CASK p.Asp424Gly Uncertain significance ★★ ⚠ same condition
CASK p.Asp445Asn Uncertain significance ★★ ⚠ 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-cys418tyr (accessed [today's date]).

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