Is CASK p.Asp424Gly (c.1271A>G) pathogenic?

CASK p.Asp424Gly (c.1271A>G) is classified Uncertain significance in CASK (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-11-02). AlphaMissense: likely benign (0.2602); Absent from gnomAD v4.1; Associated with Intellectual disability, CASK-related, X-linked.

What condition is associated with CASK p.Asp424Gly (c.1271A>G)?

CASK p.Asp424Gly (c.1271A>G) is associated with Intellectual disability, CASK-related, X-linked, syndromic X-linked intellectual disability Najm type (ClinVar).

How common is CASK p.Asp424Gly (c.1271A>G) in the general population?

CASK p.Asp424Gly (c.1271A>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CASK p.Asp424Gly (c.1271A>G)?

AlphaMissense predicts likely benign (score 0.2602) — an in-silico prediction, not a clinical call.

CASK p.Asp424Gly

c.1271A>G · rs2519844783 · VCV3254660

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2602 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,181,732)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Intellectual disability, CASK-related, X-linked

Computational evidence

Protein change
AlphaMissense	0.2602	likely benign
REVEL	0.217	benign-leaning
SaProt	LLR -12.10	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 1.3, phastCons 1
Regional constraint	o/e 0.50	unconstrained · MANE · 77 kb · p 1.9e-13 · regional, not allelic
Overall
CADD	23.4	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

No allele count reported in gnomAD v4.1 (AN 1,181,732). 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.Asp424Gly
Coding: c.1271A>G
MANE Select: NM_001367721
dbSNP: rs2519844783
Type: single nucleotide variant
Location: chrX:41586950 (GRCh38)
Structure: AlphaFold pLDDT 79.45 · 22 PDB
Residue 424: a UniProt-annotated variant site (found in a patient with epilepsy and pontocerebellar hypoplasia; likely pathogenic); the l27 2 domain; 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: syndromic X-linked intellectual disability Najm type

Similar variants

CASK p.Asp424Asn Uncertain significance ★ ⚠ 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.59+2T>C Pathogenic/Likely pathogenic ★★ same condition
CASK p.Arg106Ter Pathogenic ★★ same condition
CASK p.Arg255Cys 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-asp424gly (accessed [today's date]).

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