Is CASK p.Leu457= (c.1369T>C) pathogenic?

CASK p.Leu457= (c.1369T>C) is classified Likely benign in CASK (ClinVar, Single submitter, 1 submitter; last evaluated 2026-02-03). Ultra-rare (popmax 0.0122%, afr); Associated with Intellectual disability, CASK-related, X-linked.

What condition is associated with CASK p.Leu457= (c.1369T>C)?

CASK p.Leu457= (c.1369T>C) is associated with Intellectual disability, CASK-related, X-linked (ClinVar).

How common is CASK p.Leu457= (c.1369T>C) in the general population?

CASK p.Leu457= (c.1369T>C) is ultra-rare (popmax 0.0122%, afr) (gnomAD).

CASK p.Leu457=

c.1369T>C · rs371870820 · VCV1100860

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0122%, 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 0.006	GERP -2.9
Overall
CADD	4.647	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0122% African / African-American · 7/57,203 alleles

Filtering AF 0.00567% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00406%

Overall 0.00207% 25/1,206,810 alleles · ultra-rare exomes 20/1,094,694 · genomes 5/112,116 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0122%	8,172
Remaining individualsnot grpmax-eligible	0.00211%	47,482
European (non-Finnish)	0.00179%	55,763
South Asian	0.00176%	56,711

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.Leu457=
Coding: c.1369T>C
MANE Select: NM_001367721
dbSNP: rs371870820
Type: single nucleotide variant
Location: chrX:41578474 (GRCh38)
Structure: AlphaFold pLDDT 79.45 · 22 PDB
Residue 457: 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-leu457 (accessed [today's date]).

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