Is CASK p.Met94Ile (c.282G>A) pathogenic?

CASK p.Met94Ile (c.282G>A) is classified Uncertain significance in CASK (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-25). AlphaMissense: likely pathogenic (0.9904); Absent from gnomAD v4.1.

How common is CASK p.Met94Ile (c.282G>A) in the general population?

CASK p.Met94Ile (c.282G>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CASK p.Met94Ile (c.282G>A)?

AlphaMissense predicts likely pathogenic (score 0.9904) — an in-silico prediction, not a clinical call.

CASK p.Met94Ile

c.282G>A · rs2519520842 · VCV2576029

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9904 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9904	likely pathogenic
REVEL	0.336	indeterminate
SaProt	LLR -7.43	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	Δ0.84	acceptor gain · deltas
Pangolin	Δ0.36	gain · loss 0.03 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.7	GERP 2, phastCons 1
Regional constraint	o/e 0.31	constrained · MANE · 286 kb · p 1e-25 · regional, not allelic
Overall
CADD	35.0	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

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.Met94Ile
Coding: c.282G>A
MANE Select: NM_001367721
dbSNP: rs2519520842
Type: single nucleotide variant
Location: chrX:41745598 (GRCh38)
Structure: AlphaFold pLDDT 79.45 · 22 PDB
Residue 94: the protein kinase domain; a UniProt-annotated variant site (found in a patient with epilepsy and pontocerebellar hypoplasia; likely pathogenic)

Full CASK gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CASK p.Met94Thr Uncertain significance ★ ⚠ same residue
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.2317+5G>A Pathogenic/Likely pathogenic ★★ same type
CASK c.2521-2A>G Pathogenic/Likely pathogenic ★★ same type
CASK c.59+2T>C Pathogenic/Likely pathogenic ★★ same type
CASK p.Arg106Ter 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-met94ile (accessed [today's date]).

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