Is CASK p.Leu759= (c.2277C>T) pathogenic?

CASK p.Leu759= (c.2277C>T) is classified Conflicting classifications of pathogenicity in CASK (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-11-24). Very rare (popmax 0.00652%, amr); Associated with Intellectual disability, CASK-related, X-linked.

What condition is associated with CASK p.Leu759= (c.2277C>T)?

CASK p.Leu759= (c.2277C>T) is associated with Intellectual disability, CASK-related, X-linked (ClinVar).

How common is CASK p.Leu759= (c.2277C>T) in the general population?

CASK p.Leu759= (c.2277C>T) is very rare (popmax 0.00652%, amr) (gnomAD).

CASK p.Leu759=

c.2277C>T · rs758345399 · VCV434589

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00652%, amr)

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 3.4	GERP -2.9, phastCons 1
Overall
CADD	8.53	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00652% Admixed American · 3/46,030 alleles

Filtering AF 0.00173% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000879%

Overall 0.000821% 9/1,096,326 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00652%	15,343
Remaining individualsnot grpmax-eligible	0.0021%	47,581
South Asian	0.00176%	56,970
European (non-Finnish)	0.000448%	223,464

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.Leu759=
Coding: c.2277C>T
MANE Select: NM_001367721
dbSNP: rs758345399
Type: single nucleotide variant
Location: chrX:41534746 (GRCh38)
Structure: AlphaFold pLDDT 79.45 · 22 PDB
Residue 759: a UniProt-annotated variant site (found in a patient with epilepsy and pontocerebellar hypoplasia; likely pathogenic); the guanylate kinase-like domain; the 'required for interaction with nrxn1 (via c-terminal tail)' region; 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.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-leu759 (accessed [today's date]).

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