Is CASK p.Ala2Thr (c.4G>A) pathogenic?

CASK p.Ala2Thr (c.4G>A) is classified Uncertain significance in CASK (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-07). AlphaMissense: ambiguous (0.4971); Absent from gnomAD v4.1.

How common is CASK p.Ala2Thr (c.4G>A) in the general population?

CASK p.Ala2Thr (c.4G>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CASK p.Ala2Thr (c.4G>A)?

AlphaMissense predicts ambiguous (score 0.4971) — an in-silico prediction, not a clinical call.

CASK p.Ala2Thr

c.4G>A · rs2520195945 · VCV3252396

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4971 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4971	ambiguous
REVEL	0.152	moderately benign-leaning
SaProt	LLR -7.38	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.8, phastCons 1
Regional constraint	o/e 0.31	constrained · MANE · 286 kb · p 1e-25 · regional, not allelic
Overall
CADD	24.6	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.Ala2Thr
Coding: c.4G>A
MANE Select: NM_001367721
dbSNP: rs2520195945
Type: single nucleotide variant
Location: chrX:41922985 (GRCh38)
Structure: AlphaFold pLDDT 79.45 · 22 PDB
Residue 2: an α-helix

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

Similar variants

CASK p.Ala2= Likely benign ★ 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-ala2thr (accessed [today's date]).

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