Is CASK p.Thr863Ile (c.2588C>T) pathogenic?

CASK p.Thr863Ile (c.2588C>T) is classified Likely benign in CASK (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-01). AlphaMissense: likely benign (0.3058); Ultra-rare (popmax 0.011%, amr); Associated with Intellectual disability, CASK-related, X-linked.

What condition is associated with CASK p.Thr863Ile (c.2588C>T)?

CASK p.Thr863Ile (c.2588C>T) is associated with Intellectual disability, CASK-related, X-linked (ClinVar).

How common is CASK p.Thr863Ile (c.2588C>T) in the general population?

CASK p.Thr863Ile (c.2588C>T) is ultra-rare (popmax 0.011%, amr) (gnomAD).

What do computational predictors say about CASK p.Thr863Ile (c.2588C>T)?

AlphaMissense predicts likely benign (score 0.3058) — an in-silico prediction, not a clinical call.

CASK p.Thr863Ile

c.2588C>T · rs966502877 · VCV470210

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3058 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.011%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Intellectual disability, CASK-related, X-linked

Computational evidence

Protein change
AlphaMissense	0.3058	likely benign
REVEL	0.353	indeterminate
SaProt	LLR -7.68	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.3, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 22 kb · p 7.7e-05 · regional, not allelic
Overall
CADD	24.9	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 0.011% Admixed American · 5/45,348 alleles

Filtering AF 0.00431% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00273%

Overall 0.000503% 6/1,192,756 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.011%	9,070
South Asian	0.00179%	55,831

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.Thr863Ile
Coding: c.2588C>T
MANE Select: NM_001367721
dbSNP: rs966502877
Type: single nucleotide variant
Location: chrX:41523967 (GRCh38)
Structure: AlphaFold pLDDT 79.45 · 22 PDB
Residue 863: a UniProt-annotated variant site (found in a patient with epilepsy and pontocerebellar hypoplasia; likely pathogenic); the guanylate kinase-like domain; the 'required for interaction with nrxn1 (via c-terminal tail)' region

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.Thr863= Likely benign ★ same residue
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

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-thr863ile (accessed [today's date]).

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