Is CASK p.Ser319= (c.957A>G) pathogenic?

CASK p.Ser319= (c.957A>G) is classified Likely benign in CASK (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-13). Very rare (popmax 0.00176%, sas); Associated with Intellectual disability, CASK-related, X-linked.

What condition is associated with CASK p.Ser319= (c.957A>G)?

CASK p.Ser319= (c.957A>G) is associated with Intellectual disability, CASK-related, X-linked (ClinVar).

How common is CASK p.Ser319= (c.957A>G) in the general population?

CASK p.Ser319= (c.957A>G) is very rare (popmax 0.00176%, sas) (gnomAD).

CASK p.Ser319=

c.957A>G · rs2519037904 · VCV2881114

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00176%, 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 -0.82	GERP -2.4, phastCons 0.005
Overall
CADD	7.022	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00176% South Asian · 1/56,876 alleles

Overall 9.15e-05% 1/1,093,067 alleles · very 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.Ser319=
Coding: c.957A>G
MANE Select: NM_001367721
dbSNP: rs2519037904
Type: single nucleotide variant
Location: chrX:41626662 (GRCh38)
Structure: AlphaFold pLDDT 79.45 · 22 PDB
Residue 319: 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-ser319 (accessed [today's date]).

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