Is CASK p.Asn666fs (c.1997dup) pathogenic?

CASK p.Asn666fs (c.1997dup) is classified Pathogenic in CASK (ClinVar, Single submitter, 1 submitter; last evaluated 2019-08-06). Absent from gnomAD v4.1; Associated with syndromic X-linked intellectual disability Najm type.

What condition is associated with CASK p.Asn666fs (c.1997dup)?

CASK p.Asn666fs (c.1997dup) is associated with syndromic X-linked intellectual disability Najm type (ClinVar).

How common is CASK p.Asn666fs (c.1997dup) in the general population?

CASK p.Asn666fs (c.1997dup) is absent from gnomAD v4.1 (gnomAD).

How is X-linked intellectual disability, Najm type inherited?

Typically X-linked dominant (Orphanet). A genetic counselor can assess individual risk for a family.

CASK p.Asn666fs

c.1997dup · rs1602253464 · VCV828187

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 1,207,912)

Conditions

syndromic X-linked intellectual disability Najm type

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 21 of 27
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.36	GERP -2.2, phastCons 0.51

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 1,207,912). 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.Asn666fs
Coding: c.1997dup
MANE Select: NM_001367721
dbSNP: rs1602253464
Type: Duplication
Location: chrX:41553760 (GRCh38)
Structure: AlphaFold pLDDT 79.45 · 22 PDB
Residue 666: a UniProt-annotated variant site (found in a patient with epilepsy and pontocerebellar hypoplasia; likely pathogenic); the sh3 domain; 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

syndromic X-linked intellectual disability Najm type — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For X-linked intellectual disability, Najm type (Orphanet):

Inheritance: X-linked dominant
Onset: Infancy, Neonatal

Similar variants

CASK c.1315-4_1315-1dup Likely pathogenic ★ same condition
CASK p.Ala187fs Likely pathogenic ★ same condition
CASK p.Gly306fs Pathogenic ★ same condition
CASK p.Met186fs Pathogenic ★ same condition
CASK p.Pro329fs Likely pathogenic ★ same condition
CASK p.Ser172fs Likely pathogenic ★ same condition
CASK p.Ile524_His525insMetIle Uncertain significance ★ same condition
CASK p.Tyr708fs Pathogenic/Likely pathogenic 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-asn666fs (accessed [today's date]).

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