Is CASK p.Leu383= (c.1149A>G) pathogenic?

CASK p.Leu383= (c.1149A>G) is classified Likely benign in CASK (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-01). Ultra-rare (popmax 0.023%, mid); Associated with Intellectual disability, CASK-related, X-linked.

What condition is associated with CASK p.Leu383= (c.1149A>G)?

CASK p.Leu383= (c.1149A>G) is associated with Intellectual disability, CASK-related, X-linked (ClinVar).

How common is CASK p.Leu383= (c.1149A>G) in the general population?

CASK p.Leu383= (c.1149A>G) is ultra-rare (popmax 0.023%, mid) (gnomAD).

CASK p.Leu383=

c.1149A>G · rs2066019067 · VCV1567439

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.023%, mid)

Conditions

Intellectual disability, CASK-related, X-linked

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.62	GERP 0.063, phastCons 1
Overall
CADD	7.943	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.023% Middle Eastern · 1/4,353 alleles

Filtering AF 0.000909% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000711%

Overall 0.00137% 15/1,095,604 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.023%	4,353
European (non-Finnish)	0.00157%	63,804

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.Leu383=
Coding: c.1149A>G
MANE Select: NM_001367721
dbSNP: rs2066019067
Type: single nucleotide variant
Location: chrX:41609910 (GRCh38)
Structure: AlphaFold pLDDT 79.45 · 22 PDB
Residue 383: the l27 1 domain; 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-leu383 (accessed [today's date]).

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