Is CASK p.Ala359= (c.1077G>A) pathogenic?

CASK p.Ala359= (c.1077G>A) is classified Conflicting classifications of pathogenicity in CASK (ClinVar, Conflicting submitters, 9 submitters; last evaluated 2026-01-28). Rare (popmax 0.157%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CASK p.Ala359= (c.1077G>A)?

CASK p.Ala359= (c.1077G>A) is associated with Inborn genetic diseases (ClinVar).

How common is CASK p.Ala359= (c.1077G>A) in the general population?

CASK p.Ala359= (c.1077G>A) is rare (popmax 0.157%, nfe) (gnomAD).

CASK p.Ala359=

c.1077G>A · rs145641295 · VCV194051

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 9 submitters

gnomAD v4.1

Rare

rare (popmax 0.157%, nfe)

Conditions

Inborn genetic diseases

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 -0.14	GERP -2.5, phastCons 0.75
Overall
CADD	3.652	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.157% European (non-Finnish) · 1,397/892,536 alleles

Filtering AF 0.15% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.147%

Overall 0.126% 1,521/1,207,236 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.157%	639
Remaining individualsnot grpmax-eligible	0.139%	720
Admixed American	0.0634%	1,578
East Asian	0.0207%	4,826
African / African-American	0.0157%	6,362
Finnishnot grpmax-eligible	0.015%	6,656
Ashkenazi Jewishnot grpmax-eligible	0.00908%	11,008
South Asian	0.00705%	14,187

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.Ala359=
Coding: c.1077G>A
MANE Select: NM_001367721
dbSNP: rs145641295
Type: single nucleotide variant
Location: chrX:41609982 (GRCh38)
Structure: AlphaFold pLDDT 79.45 · 22 PDB
Residue 359: 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

Disease context

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

Similar variants

CASK p.Ala359Val Uncertain significance ★★ ⚠ 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
CASK p.Glu662Asp 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-ala359 (accessed [today's date]).

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