Is CASK p.Arg281Cys (c.841C>T) pathogenic?

CASK p.Arg281Cys (c.841C>T) is classified Uncertain significance in CASK (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-02). AlphaMissense: likely pathogenic (0.8601); Very rare (popmax 0.00179%, sas).

How common is CASK p.Arg281Cys (c.841C>T) in the general population?

CASK p.Arg281Cys (c.841C>T) is very rare (popmax 0.00179%, sas) (gnomAD).

What do computational predictors say about CASK p.Arg281Cys (c.841C>T)?

AlphaMissense predicts likely pathogenic (score 0.8601) — an in-silico prediction, not a clinical call.

CASK p.Arg281Cys

c.841C>T · VCV4538628

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8601 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00179%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.8601	likely pathogenic
REVEL	0.373	indeterminate
SaProt	LLR -10.30	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 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.31	constrained · MANE · 286 kb · p 1e-25 · regional, not allelic
Overall
CADD	29.6	PHRED · no single calibrated threshold — expert panels disagree

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

Grpmax group 0.00179% South Asian · 1/55,944 alleles

Overall 9.47e-05% 1/1,056,154 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.Arg281Cys
Coding: c.841C>T
MANE Select: NM_001367721
Type: single nucleotide variant
Location: chrX:41636652 (GRCh38)
Structure: AlphaFold pLDDT 79.45 · 22 PDB
Residue 281: 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

Similar variants

CASK p.Arg281His Uncertain significance ★ ⚠ same residue
CASK c.1015+1G>A Pathogenic ★★ same type
CASK c.1315-1G>A Pathogenic/Likely pathogenic ★★ same type
CASK c.2317+1G>A Pathogenic/Likely pathogenic ★★ same type
CASK c.2317+5G>A Pathogenic/Likely pathogenic ★★ same type
CASK c.2521-2A>G Pathogenic/Likely pathogenic ★★ same type
CASK c.59+2T>C Pathogenic/Likely pathogenic ★★ same type
CASK p.Arg106Ter Pathogenic ★★ same type

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-arg281cys (accessed [today's date]).

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