Is CASK p.Met523fs (c.1565dup) pathogenic?

CASK p.Met523fs (c.1565dup) is classified Likely pathogenic in CASK (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-19). Absent from gnomAD v4.1.

How common is CASK p.Met523fs (c.1565dup) in the general population?

CASK p.Met523fs (c.1565dup) is absent from gnomAD v4.1 (gnomAD).

CASK p.Met523fs

c.1565dup · rs2519796963 · VCV2438847

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,171,091)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 16 of 27
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 4	GERP 1, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

No allele count reported in gnomAD v4.1 (AN 1,171,091). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: CASK
Protein: p.Met523fs
Coding: c.1565dup
MANE Select: NM_001367721
dbSNP: rs2519796963
Type: Duplication
Location: chrX:41569684 (GRCh38)
Structure: AlphaFold pLDDT 79.45 · 22 PDB
Residue 523: a UniProt-annotated variant site (found in a patient with epilepsy and pontocerebellar hypoplasia; likely pathogenic); the pdz domain; an α-helix; the 'required for interaction with nrxn1 (via c-terminal tail)' region

Full CASK gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CASK p.Met523Thr Uncertain significance ★ ⚠ same residue
CASK c.1504-6dup Benign/Likely benign ★★ same type
CASK c.1806+17dup Likely benign ★★ same type
CASK c.2521-11dup Benign/Likely benign ★★ same type
CASK c.1156-4408_1503+2676dup Likely pathogenic ★ same type
CASK c.1315-4_1315-1dup Likely pathogenic ★ same type
CASK p.Ala187fs Likely pathogenic ★ same type
CASK p.Asn666fs Pathogenic ★ same type

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-met523fs (accessed [today's date]).

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