Is CASK p.Leu723= (c.2169A>G) pathogenic?

CASK p.Leu723= (c.2169A>G) is classified Likely pathogenic in CASK (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-23). Absent from gnomAD v4.1; Associated with syndromic X-linked intellectual disability Najm type.

What condition is associated with CASK p.Leu723= (c.2169A>G)?

CASK p.Leu723= (c.2169A>G) is associated with syndromic X-linked intellectual disability Najm type (ClinVar).

How common is CASK p.Leu723= (c.2169A>G) in the general population?

CASK p.Leu723= (c.2169A>G) is absent from gnomAD v4.1 (gnomAD).

How is X-linked intellectual disability, Najm type inherited?

Typically X-linked dominant (Orphanet). A genetic counselor can assess individual risk for a family.

CASK p.Leu723=

c.2169A>G · rs2519702084 · VCV2444142

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

syndromic X-linked intellectual disability Najm type

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 7.9	GERP 0.55, phastCons 1
Overall
CADD	14.71	PHRED · no single calibrated threshold — expert panels disagree

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.Leu723=
Coding: c.2169A>G
MANE Select: NM_001367721
dbSNP: rs2519702084
Type: single nucleotide variant
Location: chrX:41534960 (GRCh38)
Structure: AlphaFold pLDDT 79.45 · 22 PDB
Residue 723: 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

syndromic X-linked intellectual disability Najm type — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For X-linked intellectual disability, Najm type (Orphanet):

Inheritance: X-linked dominant
Onset: Infancy, Neonatal

Similar variants

CASK c.1015+1G>A Pathogenic ★★ same condition
CASK c.1315-1G>A Pathogenic/Likely pathogenic ★★ same condition
CASK c.2317+1G>A Pathogenic/Likely pathogenic ★★ same condition
CASK c.2317+5G>A Pathogenic/Likely pathogenic ★★ same condition
CASK c.59+2T>C Pathogenic/Likely pathogenic ★★ same condition
CASK p.Arg106Ter Pathogenic ★★ same condition
CASK p.Arg255Cys Pathogenic/Likely pathogenic ★★ same condition
CASK p.Arg27Ter Pathogenic ★★ 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-leu723 (accessed [today's date]).

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