Is CASK p.Lys877del (c.2629_2631del) pathogenic?

CASK p.Lys877del (c.26292631del) is classified Uncertain significance in CASK (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-06-14). Very rare (popmax 0.000112%, nfe); Associated with CASK-related disorder.

What condition is associated with CASK p.Lys877del (c.2629_2631del)?

CASK p.Lys877del (c.2629_2631del) is associated with CASK-related disorder (ClinVar).

How common is CASK p.Lys877del (c.2629_2631del) in the general population?

CASK p.Lys877del (c.2629_2631del) is very rare (popmax 0.000112%, nfe) (gnomAD).

CASK p.Lys877del

c.2629_2631del · rs2519652412 · VCV2628483

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000112%, nfe)

Conditions

CASK-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.7	GERP 1.9, phastCons 1

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000112% European (non-Finnish) · 1/892,741 alleles

Overall 8.28e-05% 1/1,207,926 alleles · very rare exomes 1/1,094,435 · genomes 0/113,491 · joint denominator

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.Lys877del
Coding: c.2629_2631del
MANE Select: NM_001367721
dbSNP: rs2519652412
Type: Deletion
Location: chrX:41520570 (GRCh38)
Structure: AlphaFold pLDDT 79.45 · 22 PDB
Residue 877: a UniProt-annotated variant site (found in a patient with epilepsy and pontocerebellar hypoplasia; likely pathogenic); the guanylate kinase-like domain; the 'required for interaction with nrxn1 (via c-terminal tail)' region; an α-helix

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

Disease context

CASK-related disorder

Similar variants

CASK p.Thr548fs Pathogenic/Likely pathogenic ★★ same condition
CASK c.1504-2_1504-1del Likely pathogenic ★ same condition
CASK p.Ala814fs Likely pathogenic ★ same condition
CASK p.His520fs Likely pathogenic ★ same condition
CASK p.Ile137fs Likely pathogenic ★ same condition
CASK p.Lys393fs Likely pathogenic ★ same condition
CASK p.Arg28Ter Pathogenic ★★ same condition
CASK p.Arg489Trp 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-lys877del (accessed [today's date]).

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