Is CASK p.Met555fs (c.1663del) pathogenic?

CASK p.Met555fs (c.1663del) is classified Pathogenic in CASK (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-24). Absent from gnomAD v4.1; Associated with Intellectual disability, CASK-related, X-linked.

What condition is associated with CASK p.Met555fs (c.1663del)?

CASK p.Met555fs (c.1663del) is associated with Intellectual disability, CASK-related, X-linked (ClinVar).

How common is CASK p.Met555fs (c.1663del) in the general population?

CASK p.Met555fs (c.1663del) is absent from gnomAD v4.1 (gnomAD).

CASK p.Met555fs

c.1663del · rs2519772661 · VCV2840571

Pathogenic Single submitter

Classification

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 1,188,620)

Conditions

Intellectual disability, CASK-related, X-linked

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 17 of 27
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 9.3	GERP 0.71, 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 1,188,620). 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.Met555fs
Coding: c.1663del
MANE Select: NM_001367721
dbSNP: rs2519772661
Type: Deletion
Location: chrX:41561564 (GRCh38)
Structure: AlphaFold pLDDT 79.45 · 22 PDB
Residue 555: 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

Disease context

Intellectual disability, CASK-related, X-linked — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CASK c.1504-6del Benign/Likely benign ★★ same condition
CASK p.Arg526fs Pathogenic ★ same condition
CASK p.Glu153fs Pathogenic ★ same condition
CASK p.His358fs Pathogenic ★ same condition
CASK c.2155+5_2155+6del Uncertain significance ★ same condition
CASK p.Asp10_Glu16del Uncertain significance ★ same condition
CASK p.Met555Ile Uncertain significance ★ ⚠ same residue
CASK c.1034-5del Benign ★ 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-met555fs (accessed [today's date]).

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