Is CASK p.Pro199Leu (c.596C>T) pathogenic?

CASK p.Pro199Leu (c.596C>T) is classified Uncertain significance in CASK (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-28). AlphaMissense: likely pathogenic (0.9722); Absent from gnomAD v4.1; Associated with Intellectual disability, CASK-related, X-linked.

What condition is associated with CASK p.Pro199Leu (c.596C>T)?

CASK p.Pro199Leu (c.596C>T) is associated with Intellectual disability, CASK-related, X-linked (ClinVar).

How common is CASK p.Pro199Leu (c.596C>T) in the general population?

CASK p.Pro199Leu (c.596C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CASK p.Pro199Leu (c.596C>T)?

AlphaMissense predicts likely pathogenic (score 0.9722) — an in-silico prediction, not a clinical call.

CASK p.Pro199Leu

c.596C>T · rs1569379968 · VCV566452

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9722 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Intellectual disability, CASK-related, X-linked

Computational evidence

Protein change
AlphaMissense	0.9722	likely pathogenic
REVEL	0.584	indeterminate
SaProt	LLR -15.43	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 1.7, phastCons 1
Regional constraint	o/e 0.31	constrained · MANE · 286 kb · p 1e-25 · regional, not allelic
Overall
CADD	28.8	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CASK
Protein: p.Pro199Leu
Coding: c.596C>T
MANE Select: NM_001367721
dbSNP: rs1569379968
Type: single nucleotide variant
Location: chrX:41665389 (GRCh38)
Structure: AlphaFold pLDDT 79.45 · 22 PDB
Residue 199: 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

Intellectual disability, CASK-related, X-linked — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CASK p.Pro199= 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-pro199leu (accessed [today's date]).

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