Is CASK p.Cys132Ter (c.396C>A) pathogenic?

CASK p.Cys132Ter (c.396C>A) is classified Likely pathogenic in CASK (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-16). Absent from gnomAD v4.1; Associated with syndromic X-linked intellectual disability Najm type.

What condition is associated with CASK p.Cys132Ter (c.396C>A)?

CASK p.Cys132Ter (c.396C>A) is associated with syndromic X-linked intellectual disability Najm type (ClinVar).

How common is CASK p.Cys132Ter (c.396C>A) in the general population?

CASK p.Cys132Ter (c.396C>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.

CASK p.Cys132Ter

c.396C>A · VCV4759222

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,185,346)

Conditions

syndromic X-linked intellectual disability Najm type

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 5 of 27
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.5	GERP 0.82, phastCons 1
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

No allele count reported in gnomAD v4.1 (AN 1,185,346). 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.Cys132Ter
Coding: c.396C>A
MANE Select: NM_001367721
Type: single nucleotide variant
Location: chrX:41739417 (GRCh38)
Structure: AlphaFold pLDDT 79.45 · 22 PDB
Residue 132: 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

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

Inheritance: X-linked dominant
Onset: Infancy, Neonatal

Similar variants

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
CASK p.Arg27Ter 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-cys132ter (accessed [today's date]).

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