Is CASK p.Arg28Ter (c.82C>T) pathogenic?

CASK p.Arg28Ter (c.82C>T) is classified Pathogenic in CASK (ClinVar, Multiple submitters, 11 submitters; last evaluated 2025-07-21). Very rare (popmax 0.000113%, nfe); Associated with CASK-related syndromic intellectual disability.

What condition is associated with CASK p.Arg28Ter (c.82C>T)?

CASK p.Arg28Ter (c.82C>T) is associated with CASK-related syndromic intellectual disability, FG syndrome 4, syndromic X-linked intellectual disability Najm type (ClinVar).

How common is CASK p.Arg28Ter (c.82C>T) in the general population?

CASK p.Arg28Ter (c.82C>T) is very rare (popmax 0.000113%, nfe) (gnomAD).

CASK p.Arg28Ter

c.82C>T · rs587783370 · VCV158086

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 11 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000113%, nfe)

Conditions

CASK-related syndromic intellectual disability

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 2 of 27
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 2.9, phastCons 1
Overall
CADD	38.0	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

Grpmax group 0.000113% European (non-Finnish) · 1/882,118 alleles

Overall 0.000902% 1/110,890 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.Arg28Ter
Coding: c.82C>T
MANE Select: NM_001367721
dbSNP: rs587783370
Type: single nucleotide variant
Location: chrX:41853205 (GRCh38)
Structure: AlphaFold pLDDT 79.45 · 22 PDB
Residue 28: the protein kinase domain; a UniProt-annotated variant site (found in a patient with epilepsy and pontocerebellar hypoplasia; likely pathogenic); a UniProt-annotated variant site (in fgs4; does not reveal significant alterations induced by the mutation substitution; causes a partial skipping of exon 2 of the protein); a β-strand

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

Disease context

CASK-related syndromic intellectual disability

Also linked: FG syndrome 4 syndromic X-linked intellectual disability Najm type

Similar variants

CASK p.Arg28Leu Pathogenic same residue
GPR82 p.Val28Ala Uncertain significance ★ same residue
CASK p.Arg28= Likely benign ★ 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

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-arg28ter (accessed [today's date]).

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