Is CASK p.Ala283Thr (c.847G>A) pathogenic?

CASK p.Ala283Thr (c.847G>A) is classified Uncertain significance in CASK (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-06-04). AlphaMissense: ambiguous (0.4153); Very rare (popmax 0.00218%, amr); Associated with FG syndrome 4.

What condition is associated with CASK p.Ala283Thr (c.847G>A)?

CASK p.Ala283Thr (c.847G>A) is associated with FG syndrome 4 (ClinVar).

How common is CASK p.Ala283Thr (c.847G>A) in the general population?

CASK p.Ala283Thr (c.847G>A) is very rare (popmax 0.00218%, amr) (gnomAD).

What do computational predictors say about CASK p.Ala283Thr (c.847G>A)?

AlphaMissense predicts ambiguous (score 0.4153) — an in-silico prediction, not a clinical call.

CASK p.Ala283Thr

c.847G>A · rs1012863843 · VCV1421797

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4153 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00218%, amr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

FG syndrome 4

Computational evidence

Protein change
AlphaMissense	0.4153	ambiguous
REVEL	0.18	moderately benign-leaning
SaProt	LLR -9.79	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 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.50	unconstrained · MANE · 77 kb · p 1.9e-13 · regional, not allelic
Overall
CADD	24.2	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 0.00218% Admixed American · 1/45,901 alleles

Overall 0.000282% 3/1,064,304 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00218%	45,901
Remaining individualsnot grpmax-eligible	0.00215%	46,559
European (non-Finnish)	0.000116%	864,730

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.Ala283Thr
Coding: c.847G>A
MANE Select: NM_001367721
dbSNP: rs1012863843
Type: single nucleotide variant
Location: chrX:41636646 (GRCh38)
Structure: AlphaFold pLDDT 79.45 · 22 PDB
Residue 283: 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

FG syndrome 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CASK c.2317+5G>A Pathogenic/Likely pathogenic ★★ same condition
CASK c.2521-2A>G Pathogenic/Likely pathogenic ★★ same condition
CASK c.59+2T>C Pathogenic/Likely pathogenic ★★ same condition
CASK p.Arg28Ter Pathogenic ★★ same condition
CASK p.Arg489Gln Pathogenic/Likely pathogenic ★★ same condition
CASK p.Arg613Ter Pathogenic/Likely pathogenic ★★ same condition
CASK p.Glu102Gly Pathogenic/Likely pathogenic ★★ same condition
CASK p.Tyr282Ter Pathogenic ★★ 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-ala283thr (accessed [today's date]).

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