Is CASK p.Leu340Ile (c.1018C>A) pathogenic?

CASK p.Leu340Ile (c.1018C>A) is classified Uncertain significance in CASK (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-03). AlphaMissense: likely benign (0.1983); Absent from gnomAD v4.1; Associated with Intellectual disability, CASK-related, X-linked.

What condition is associated with CASK p.Leu340Ile (c.1018C>A)?

CASK p.Leu340Ile (c.1018C>A) is associated with Intellectual disability, CASK-related, X-linked (ClinVar).

How common is CASK p.Leu340Ile (c.1018C>A) in the general population?

CASK p.Leu340Ile (c.1018C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CASK p.Leu340Ile (c.1018C>A)?

AlphaMissense predicts likely benign (score 0.1983) — an in-silico prediction, not a clinical call.

CASK p.Leu340Ile

c.1018C>A · VCV3658706

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1983 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,194,873)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Intellectual disability, CASK-related, X-linked

Computational evidence

Protein change
AlphaMissense	0.1983	likely benign
REVEL	0.208	benign-leaning
SaProt	LLR -6.84	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.6, phastCons 1
Regional constraint	o/e 0.50	unconstrained · MANE · 77 kb · p 1.9e-13 · regional, not allelic
Overall
CADD	24.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 1,194,873). 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.Leu340Ile
Coding: c.1018C>A
MANE Select: NM_001367721
Type: single nucleotide variant
Location: chrX:41622632 (GRCh38)
Structure: AlphaFold pLDDT 79.45 · 22 PDB
Residue 340: a UniProt-annotated variant site (found in a patient with epilepsy and pontocerebellar hypoplasia; likely pathogenic)

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-leu340ile (accessed [today's date]).

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