Is CASK p.Leu14= (c.42G>C) pathogenic?

CASK p.Leu14= (c.42G>C) is classified Conflicting classifications of pathogenicity in CASK (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-03-19). Ultra-rare (popmax 0.021%, afr); Associated with Intellectual disability, CASK-related, X-linked.

What condition is associated with CASK p.Leu14= (c.42G>C)?

CASK p.Leu14= (c.42G>C) is associated with Intellectual disability, CASK-related, X-linked (ClinVar).

How common is CASK p.Leu14= (c.42G>C) in the general population?

CASK p.Leu14= (c.42G>C) is ultra-rare (popmax 0.021%, afr) (gnomAD).

CASK p.Leu14=

c.42G>C · rs377590077 · VCV596572

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.021%, afr)

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 3.3	GERP 1.1, phastCons 1
Overall
CADD	12.06	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.021% African / African-American · 12/57,204 alleles

Filtering AF 0.012% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00949%

Overall 0.00116% 14/1,209,413 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.021%	4,767
Remaining individualsnot grpmax-eligible	0.0021%	47,573
South Asian	0.00176%	56,811

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.Leu14=
Coding: c.42G>C
MANE Select: NM_001367721
dbSNP: rs377590077
Type: single nucleotide variant
Location: chrX:41922947 (GRCh38)
Structure: AlphaFold pLDDT 79.45 · 22 PDB
Residue 14: the protein kinase domain; a β-strand

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-leu14 (accessed [today's date]).

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