Is CASK p.Lys366Asn (c.1098G>T) pathogenic?

CASK p.Lys366Asn (c.1098G>T) is classified Uncertain significance in CASK (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-06-26). AlphaMissense: likely pathogenic (0.58); Very rare (popmax 0.0035%, afr).

How common is CASK p.Lys366Asn (c.1098G>T) in the general population?

CASK p.Lys366Asn (c.1098G>T) is very rare (popmax 0.0035%, afr) (gnomAD).

What do computational predictors say about CASK p.Lys366Asn (c.1098G>T)?

AlphaMissense predicts likely pathogenic (score 0.58) — an in-silico prediction, not a clinical call.

CASK p.Lys366Asn

c.1098G>T · rs1205947875 · VCV595283

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.58 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0035%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.58	likely pathogenic
REVEL	0.148	moderately benign-leaning
SaProt	LLR -7.34	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.54	GERP -1.6, phastCons 1
Regional constraint	o/e 0.50	unconstrained · MANE · 77 kb · p 1.9e-13 · regional, not allelic
Overall
CADD	18.96	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 0.0035% African / African-American · 2/57,140 alleles

Filtering AF 0.000581% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000217%

Overall 0.000166% 2/1,205,916 alleles · very rare

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.Lys366Asn
Coding: c.1098G>T
MANE Select: NM_001367721
dbSNP: rs1205947875
Type: single nucleotide variant
Location: chrX:41609961 (GRCh38)
Structure: AlphaFold pLDDT 79.45 · 22 PDB
Residue 366: the l27 1 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 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
CASK p.Arg255Cys 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-lys366asn (accessed [today's date]).

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