Is CASK p.Arg430Cys (c.1288C>T) pathogenic?

CASK p.Arg430Cys (c.1288C>T) is classified Likely benign in CASK (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-02-19). AlphaMissense: likely benign (0.1456); Very rare (popmax 0.00716%, sas); Associated with Intellectual disability, CASK-related, X-linked.

What condition is associated with CASK p.Arg430Cys (c.1288C>T)?

CASK p.Arg430Cys (c.1288C>T) is associated with Intellectual disability, CASK-related, X-linked (ClinVar).

How common is CASK p.Arg430Cys (c.1288C>T) in the general population?

CASK p.Arg430Cys (c.1288C>T) is very rare (popmax 0.00716%, sas) (gnomAD).

What do computational predictors say about CASK p.Arg430Cys (c.1288C>T)?

AlphaMissense predicts likely benign (score 0.1456) — an in-silico prediction, not a clinical call.

CASK p.Arg430Cys

c.1288C>T · rs149798861 · VCV1105473

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1456 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00716%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Intellectual disability, CASK-related, X-linked

Computational evidence

Protein change
AlphaMissense	0.1456	likely benign
REVEL	0.48	indeterminate
SaProt	LLR -9.19	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 9.8	GERP 1.3, phastCons 1
Regional constraint	o/e 0.50	unconstrained · MANE · 77 kb · p 1.9e-13 · regional, not allelic
Overall
CADD	25.0	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

Grpmax group 0.00716% South Asian · 4/55,891 alleles

Filtering AF 0.00237% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00142%

Overall 0.00119% 14/1,181,271 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00716%	13,973
European (non-Finnish)	0.00115%	87,025

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.Arg430Cys
Coding: c.1288C>T
MANE Select: NM_001367721
dbSNP: rs149798861
Type: single nucleotide variant
Location: chrX:41586933 (GRCh38)
Structure: AlphaFold pLDDT 79.45 · 22 PDB
Residue 430: 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

Similar variants

CASK p.Arg430His Benign/Likely benign ★★ same residue
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

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-arg430cys (accessed [today's date]).

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