Is CASK p.Arg824Trp (c.2470C>T) pathogenic?

CASK p.Arg824Trp (c.2470C>T) is classified Conflicting classifications of pathogenicity in CASK (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-03-12). AlphaMissense: likely pathogenic (0.5908); Very rare (popmax 0.00699%, afr); Associated with Inborn genetic diseases.

What condition is associated with CASK p.Arg824Trp (c.2470C>T)?

CASK p.Arg824Trp (c.2470C>T) is associated with Inborn genetic diseases (ClinVar).

How common is CASK p.Arg824Trp (c.2470C>T) in the general population?

CASK p.Arg824Trp (c.2470C>T) is very rare (popmax 0.00699%, afr) (gnomAD).

What do computational predictors say about CASK p.Arg824Trp (c.2470C>T)?

AlphaMissense predicts likely pathogenic (score 0.5908) — an in-silico prediction, not a clinical call.

CASK p.Arg824Trp

c.2470C>T · rs369792621 · VCV590126

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.5908 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00699%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5908	likely pathogenic
REVEL	0.605	indeterminate
SaProt	LLR -12.99	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	GERP 0.8, 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

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00699% African / African-American · 4/57,186 alleles

Filtering AF 0.00362% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00322%

Overall 0.00479% 58/1,209,912 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0147%	6,799
African / African-Americangrpmax	0.00699%	14,296
East Asian	0.00592%	16,890
European (non-Finnish)	0.0048%	20,816
South Asian	0.00352%	28,419

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg824Trp
Coding: c.2470C>T
MANE Select: NM_001367721
dbSNP: rs369792621
Type: single nucleotide variant
Location: chrX:41531057 (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.Arg824Gln 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-arg824trp (accessed [today's date]).

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