Is CASK p.Lys665Arg (c.1994A>G) pathogenic?

CASK p.Lys665Arg (c.1994A>G) is classified Likely benign in CASK (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-22). AlphaMissense: likely benign (0.0809); Absent from gnomAD v4.1; Associated with Developmental disorder.

What condition is associated with CASK p.Lys665Arg (c.1994A>G)?

CASK p.Lys665Arg (c.1994A>G) is associated with Developmental disorder (ClinVar).

How common is CASK p.Lys665Arg (c.1994A>G) in the general population?

CASK p.Lys665Arg (c.1994A>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CASK p.Lys665Arg (c.1994A>G)?

AlphaMissense predicts likely benign (score 0.0809) — an in-silico prediction, not a clinical call.

CASK p.Lys665Arg

c.1994A>G · rs2065128581 · VCV2920701

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0809 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Developmental disorder

Computational evidence

Protein change
AlphaMissense	0.0809	likely benign
REVEL	0.496	indeterminate
SaProt	LLR -6.39	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 7.9	GERP 1.7, 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CASK
Protein: p.Lys665Arg
Coding: c.1994A>G
MANE Select: NM_001367721
dbSNP: rs2065128581
Type: single nucleotide variant
Location: chrX:41553764 (GRCh38)
Structure: AlphaFold pLDDT 79.45 · 22 PDB
Residue 665: 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

Developmental disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CASK p.Lys665Asn Uncertain significance ★ ⚠ same residue
CASK c.2317+5G>A Pathogenic/Likely pathogenic ★★ same condition
CASK p.Ala166Asp Pathogenic ★ same condition
CASK p.Ile265fs Pathogenic ★ same condition
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.2521-2A>G Pathogenic/Likely 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-lys665arg (accessed [today's date]).

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