Is CASK p.Arg824Gln (c.2471G>A) pathogenic?

CASK p.Arg824Gln (c.2471G>A) is classified Conflicting classifications of pathogenicity in CASK (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2024-03-15). AlphaMissense: likely benign (0.1961); Ultra-rare (popmax 0.0194%, sas); Associated with Inborn genetic diseases.

What condition is associated with CASK p.Arg824Gln (c.2471G>A)?

CASK p.Arg824Gln (c.2471G>A) is associated with Inborn genetic diseases (ClinVar).

How common is CASK p.Arg824Gln (c.2471G>A) in the general population?

CASK p.Arg824Gln (c.2471G>A) is ultra-rare (popmax 0.0194%, sas) (gnomAD).

What do computational predictors say about CASK p.Arg824Gln (c.2471G>A)?

AlphaMissense predicts likely benign (score 0.1961) — an in-silico prediction, not a clinical call.

CASK p.Arg824Gln

c.2471G>A · rs138646715 · VCV872826

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1961 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0194%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1961	likely benign
REVEL	0.294	indeterminate
SaProt	LLR -9.32	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP -0.28, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 22 kb · p 7.7e-05 · regional, not allelic
Overall
CADD	29.8	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 0.0194% South Asian · 11/56,844 alleles

Filtering AF 0.0108% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00835%

Overall 0.00165% 20/1,210,037 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0194%	5,168
African / African-American	0.00175%	57,227
European (non-Finnish)	0.000894%	111,890

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.Arg824Gln
Coding: c.2471G>A
MANE Select: NM_001367721
dbSNP: rs138646715
Type: single nucleotide variant
Location: chrX:41531056 (GRCh38)
Structure: AlphaFold pLDDT 79.45 · 22 PDB
Residue 824: 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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CASK p.Arg824Trp Conflicting classifications of pathogenicity ★ ⚠ same residue
CASK p.Ala300Thr Uncertain significance ★★ ⚠ same condition
CASK p.Arg560Trp Uncertain significance ★★ ⚠ same condition
CASK p.Arg766Trp Uncertain significance ★★ ⚠ same condition
CASK p.Asn31Ser Uncertain significance ★★ ⚠ same condition
CASK p.Asp330Gly Uncertain significance ★★ ⚠ same condition
CASK p.Asp498Gly Uncertain significance ★★ ⚠ same condition
CASK p.Glu662Asp Uncertain significance ★★ ⚠ 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-arg824gln (accessed [today's date]).

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