Is CASK p.Ala405= (c.1215A>G) pathogenic?

CASK p.Ala405= (c.1215A>G) is classified Conflicting classifications of pathogenicity in CASK (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-07-21). Very rare (popmax 0.000452%, nfe); Associated with Intellectual disability, CASK-related, X-linked.

What condition is associated with CASK p.Ala405= (c.1215A>G)?

CASK p.Ala405= (c.1215A>G) is associated with Intellectual disability, CASK-related, X-linked (ClinVar).

How common is CASK p.Ala405= (c.1215A>G) in the general population?

CASK p.Ala405= (c.1215A>G) is very rare (popmax 0.000452%, nfe) (gnomAD).

CASK p.Ala405=

c.1215A>G · rs1555989329 · VCV497885

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.000452%, nfe)

Conditions

Intellectual disability, CASK-related, X-linked

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.98	GERP -2.8, phastCons 1
Overall
CADD	8.909	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000452% European (non-Finnish) · 4/885,093 alleles

Filtering AF 0.000106% ClinGen BA1/BS1 input FAF95, joint · FAF99 7.1e-05%

Overall 0.000333% 4/1,200,401 alleles · very rare exomes 4/1,086,348 · genomes 0/114,053 · joint denominator

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.Ala405=
Coding: c.1215A>G
MANE Select: NM_001367721
dbSNP: rs1555989329
Type: single nucleotide variant
Location: chrX:41589533 (GRCh38)
Structure: AlphaFold pLDDT 79.45 · 22 PDB
Residue 405: a UniProt-annotated variant site (found in a patient with epilepsy and pontocerebellar hypoplasia; likely pathogenic); the l27 2 domain; an α-helix

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

Disease context

Intellectual disability, CASK-related, X-linked — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CASK p.Arg489Gln Pathogenic/Likely pathogenic ★★ same condition
CASK p.Ala359Val Uncertain significance ★★ ⚠ same condition
CASK p.Ala833Thr Uncertain significance ★★ ⚠ same condition
CASK p.Arg130Cys Uncertain significance ★★ ⚠ same condition
CASK p.Arg572His Uncertain significance ★★ ⚠ same condition
CASK p.Arg61Trp Uncertain significance ★★ ⚠ same condition
CASK p.Asp424Gly Uncertain significance ★★ ⚠ same condition
CASK p.Asp445Asn 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-ala405 (accessed [today's date]).

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