Is CASK p.Glu782Lys (c.2344G>A) pathogenic?

CASK p.Glu782Lys (c.2344G>A) is classified Uncertain significance in CASK (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-05). AlphaMissense: likely pathogenic (0.9928); Very rare (popmax 0.00527%, sas).

How common is CASK p.Glu782Lys (c.2344G>A) in the general population?

CASK p.Glu782Lys (c.2344G>A) is very rare (popmax 0.00527%, sas) (gnomAD).

What do computational predictors say about CASK p.Glu782Lys (c.2344G>A)?

AlphaMissense predicts likely pathogenic (score 0.9928) — an in-silico prediction, not a clinical call.

CASK p.Glu782Lys

c.2344G>A · VCV3369881

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9928 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00527%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9928	likely pathogenic
REVEL	0.674	pathogenic-leaning
SaProt	LLR -13.98	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.7, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 22 kb · p 7.7e-05 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00527% South Asian · 3/56,953 alleles

Filtering AF 0.0014% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000688%

Overall 0.000456% 5/1,096,892 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00527%	18,984
Finnishnot grpmax-eligible	0.00213%	46,846
European (non-Finnish)	0.000112%	894,374

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.Glu782Lys
Coding: c.2344G>A
MANE Select: NM_001367721
Type: single nucleotide variant
Location: chrX:41531183 (GRCh38)
Structure: AlphaFold pLDDT 79.45 · 22 PDB
Residue 782: 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

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

Similar variants

CASK p.Glu782Ter Pathogenic ★ same residue
CASK c.1015+1G>A Pathogenic ★★ same type
CASK c.1315-1G>A Pathogenic/Likely pathogenic ★★ same type
CASK c.2317+1G>A Pathogenic/Likely pathogenic ★★ same type
CASK c.2317+5G>A Pathogenic/Likely pathogenic ★★ same type
CASK c.2521-2A>G Pathogenic/Likely pathogenic ★★ same type
CASK c.59+2T>C Pathogenic/Likely pathogenic ★★ same type
CASK p.Arg106Ter 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-glu782lys (accessed [today's date]).

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