Is CASK p.Ser576= (c.1728G>A) pathogenic?

CASK p.Ser576= (c.1728G>A) is classified Likely benign in CASK (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-06-24). Very rare (popmax 0.00549%, nfe); Associated with Intellectual disability, CASK-related, X-linked.

What condition is associated with CASK p.Ser576= (c.1728G>A)?

CASK p.Ser576= (c.1728G>A) is associated with Intellectual disability, CASK-related, X-linked (ClinVar).

How common is CASK p.Ser576= (c.1728G>A) in the general population?

CASK p.Ser576= (c.1728G>A) is very rare (popmax 0.00549%, nfe) (gnomAD).

CASK p.Ser576=

c.1728G>A · rs56199880 · VCV2660349

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00549%, nfe)

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 -7	GERP -3.8
Overall
CADD	0.477	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00549% European (non-Finnish) · 49/892,708 alleles

Filtering AF 0.0042% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00378%

Overall 0.00439% 53/1,207,206 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00549%	18,219
Remaining individualsnot grpmax-eligible	0.00421%	23,747
East Asian	0.00296%	33,794
Admixed American	0.00218%	45,780

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.Ser576=
Coding: c.1728G>A
MANE Select: NM_001367721
dbSNP: rs56199880
Type: single nucleotide variant
Location: chrX:41559788 (GRCh38)
Structure: AlphaFold pLDDT 79.45 · 22 PDB
Residue 576: 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; the 'disordered' region

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.Ser576Leu Uncertain significance ★★ ⚠ same residue
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

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-ser576 (accessed [today's date]).

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