Is CASK p.Leu428= (c.1284A>G) pathogenic?

CASK p.Leu428= (c.1284A>G) is classified Benign in CASK (ClinVar, Single submitter, 1 submitter; last evaluated 2019-05-08). Ultra-rare (popmax 0.0124%, sas); Associated with Intellectual disability, CASK-related, X-linked.

What condition is associated with CASK p.Leu428= (c.1284A>G)?

CASK p.Leu428= (c.1284A>G) is associated with Intellectual disability, CASK-related, X-linked (ClinVar).

How common is CASK p.Leu428= (c.1284A>G) in the general population?

CASK p.Leu428= (c.1284A>G) is ultra-rare (popmax 0.0124%, sas) (gnomAD).

CASK p.Leu428=

c.1284A>G · rs766113128 · VCV1167783

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0124%, sas)

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 1.9	GERP -1.2, phastCons 1
Overall
CADD	7.974	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0124% South Asian · 7/56,322 alleles

Filtering AF 0.00575% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00411%

Overall 0.000652% 7/1,073,891 alleles · ultra-rare

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.Leu428=
Coding: c.1284A>G
MANE Select: NM_001367721
dbSNP: rs766113128
Type: single nucleotide variant
Location: chrX:41586937 (GRCh38)
Structure: AlphaFold pLDDT 79.45 · 22 PDB
Residue 428: a UniProt-annotated variant site (found in a patient with epilepsy and pontocerebellar hypoplasia; likely pathogenic); the l27 2 domain; 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-leu428 (accessed [today's date]).

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