Is CASK p.Arg641Lys (c.1922G>A) pathogenic?

CASK p.Arg641Lys (c.1922G>A) is classified Conflicting classifications of pathogenicity in CASK (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-12-15). AlphaMissense: likely benign (0.105); Rare (popmax 0.462%, eas); Associated with Inborn genetic diseases.

What condition is associated with CASK p.Arg641Lys (c.1922G>A)?

CASK p.Arg641Lys (c.1922G>A) is associated with Inborn genetic diseases (ClinVar).

How common is CASK p.Arg641Lys (c.1922G>A) in the general population?

CASK p.Arg641Lys (c.1922G>A) is rare (popmax 0.462%, eas) (gnomAD).

What do computational predictors say about CASK p.Arg641Lys (c.1922G>A)?

AlphaMissense predicts likely benign (score 0.105) — an in-silico prediction, not a clinical call.

CASK p.Arg641Lys

c.1922G>A · rs76106850 · VCV166794

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.105 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.462%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.105	likely benign
REVEL	0.225	benign-leaning
SaProt	LLR -3.96	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 0.98, phastCons 1
Regional constraint	o/e 0.29	constrained · MANE · 11 kb · p 1.3e-08 · regional, not allelic
Overall
CADD	23.9	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 0.462% East Asian · 156/33,740 alleles

Filtering AF 0.403% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.381%

Overall 0.0167% 201/1,203,462 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.462%	216
Ashkenazi Jewishnot grpmax-eligible	0.0637%	1,570
Remaining individualsnot grpmax-eligible	0.0443%	2,259
South Asian	0.00883%	11,329
European (non-Finnish)	0.000562%	177,875

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.Arg641Lys
Coding: c.1922G>A
MANE Select: NM_001367721
dbSNP: rs76106850
Type: single nucleotide variant
Location: chrX:41553836 (GRCh38)
Structure: AlphaFold pLDDT 79.45 · 22 PDB
Residue 641: a UniProt-annotated variant site (found in a patient with epilepsy and pontocerebellar hypoplasia; likely pathogenic); the sh3 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

Disease context

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

Similar variants

CASK p.Arg641Ser Uncertain significance ★ ⚠ same residue
CASK p.Arg641= Likely benign ★ 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

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-arg641lys (accessed [today's date]).

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