Is CASK p.Thr361Ile (c.1082C>T) pathogenic?

CASK p.Thr361Ile (c.1082C>T) is classified Conflicting classifications of pathogenicity in CASK (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-01-19). AlphaMissense: likely pathogenic (0.9721); Absent from gnomAD v4.1; Associated with FG syndrome 4.

What condition is associated with CASK p.Thr361Ile (c.1082C>T)?

CASK p.Thr361Ile (c.1082C>T) is associated with FG syndrome 4 (ClinVar).

How common is CASK p.Thr361Ile (c.1082C>T) in the general population?

CASK p.Thr361Ile (c.1082C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CASK p.Thr361Ile (c.1082C>T)?

AlphaMissense predicts likely pathogenic (score 0.9721) — an in-silico prediction, not a clinical call.

CASK p.Thr361Ile

c.1082C>T · rs2518967628 · VCV1676836

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9721 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

FG syndrome 4

Computational evidence

Protein change
AlphaMissense	0.9721	likely pathogenic
REVEL	0.498	indeterminate
SaProt	LLR -8.82	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.2, 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

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.Thr361Ile
Coding: c.1082C>T
MANE Select: NM_001367721
dbSNP: rs2518967628
Type: single nucleotide variant
Location: chrX:41609977 (GRCh38)
Structure: AlphaFold pLDDT 79.45 · 22 PDB
Residue 361: 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

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

Similar variants

CASK p.Thr361Ala Uncertain significance ★ ⚠ same residue
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

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-thr361ile (accessed [today's date]).

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