Is CASK p.Glu828Lys (c.2482G>A) pathogenic?

CASK p.Glu828Lys (c.2482G>A) is classified Uncertain significance in CASK (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-06-22). AlphaMissense: likely benign (0.1271); Very rare (popmax 0.00175%, sas); Associated with FG syndrome 4.

What condition is associated with CASK p.Glu828Lys (c.2482G>A)?

CASK p.Glu828Lys (c.2482G>A) is associated with FG syndrome 4 (ClinVar).

How common is CASK p.Glu828Lys (c.2482G>A) in the general population?

CASK p.Glu828Lys (c.2482G>A) is very rare (popmax 0.00175%, sas) (gnomAD).

What do computational predictors say about CASK p.Glu828Lys (c.2482G>A)?

AlphaMissense predicts likely benign (score 0.1271) — an in-silico prediction, not a clinical call.

CASK p.Glu828Lys

c.2482G>A · rs192044507 · VCV2498035

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1271 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00175%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

FG syndrome 4

Computational evidence

Protein change
AlphaMissense	0.1271	likely benign
REVEL	0.069	moderately benign-leaning
SaProt	LLR -10.79	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 0.78, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 22 kb · p 7.7e-05 · regional, not allelic
Overall
CADD	25.5	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00175% South Asian · 1/57,002 alleles

Filtering AF 8.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.5e-05%

Overall 0.000364% 4/1,097,975 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00175%	57,002
European (non-Finnish)	0.000335%	298,457

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.Glu828Lys
Coding: c.2482G>A
MANE Select: NM_001367721
dbSNP: rs192044507
Type: single nucleotide variant
Location: chrX:41531045 (GRCh38)
Structure: AlphaFold pLDDT 79.45 · 22 PDB
Residue 828: 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

FG syndrome 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CASK p.Glu828Gln Uncertain significance ★ ⚠ same residue
CASK c.2317+5G>A Pathogenic/Likely pathogenic ★★ same condition
CASK c.2521-2A>G Pathogenic/Likely pathogenic ★★ same condition
CASK c.59+2T>C Pathogenic/Likely pathogenic ★★ same condition
CASK p.Arg28Ter Pathogenic ★★ same condition
CASK p.Arg489Gln Pathogenic/Likely pathogenic ★★ same condition
CASK p.Arg613Ter Pathogenic/Likely pathogenic ★★ same condition
CASK p.Glu102Gly 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-glu828lys (accessed [today's date]).

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