Is CASK p.Val731Ala (c.2192T>C) pathogenic?

CASK p.Val731Ala (c.2192T>C) is classified Uncertain significance in CASK (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-09-27). AlphaMissense: likely pathogenic (0.9571); Absent from gnomAD v4.1; Associated with Intellectual disability, CASK-related, X-linked.

What condition is associated with CASK p.Val731Ala (c.2192T>C)?

CASK p.Val731Ala (c.2192T>C) is associated with Intellectual disability, CASK-related, X-linked (ClinVar).

How common is CASK p.Val731Ala (c.2192T>C) in the general population?

CASK p.Val731Ala (c.2192T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CASK p.Val731Ala (c.2192T>C)?

AlphaMissense predicts likely pathogenic (score 0.9571) — an in-silico prediction, not a clinical call.

CASK p.Val731Ala

c.2192T>C · rs2064855229 · VCV1315474

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9571 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,198,745)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Intellectual disability, CASK-related, X-linked

Computational evidence

Protein change
AlphaMissense	0.9571	likely pathogenic
REVEL	0.696	pathogenic-leaning
SaProt	LLR -11.05	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.7, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 22 kb · p 7.7e-05 · regional, not allelic
Overall
CADD	26.3	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

No allele count reported in gnomAD v4.1 (AN 1,198,745). 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.Val731Ala
Coding: c.2192T>C
MANE Select: NM_001367721
dbSNP: rs2064855229
Type: single nucleotide variant
Location: chrX:41534937 (GRCh38)
Structure: AlphaFold pLDDT 79.45 · 22 PDB
Residue 731: a UniProt-annotated variant site (found in a patient with epilepsy and pontocerebellar hypoplasia; likely pathogenic); the 'required for interaction with nrxn1 (via c-terminal tail)' region

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.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
CASK p.Asp445Asn 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-val731ala (accessed [today's date]).

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