Is CASK p.Ile899Thr (c.2696T>C) pathogenic?

CASK p.Ile899Thr (c.2696T>C) is classified Uncertain significance in CASK (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-28). AlphaMissense: likely pathogenic (0.9507); Very rare (popmax 0.00176%, afr).

How common is CASK p.Ile899Thr (c.2696T>C) in the general population?

CASK p.Ile899Thr (c.2696T>C) is very rare (popmax 0.00176%, afr) (gnomAD).

What do computational predictors say about CASK p.Ile899Thr (c.2696T>C)?

AlphaMissense predicts likely pathogenic (score 0.9507) — an in-silico prediction, not a clinical call.

CASK p.Ile899Thr

c.2696T>C · VCV3383674

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9507 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00176%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9507	likely pathogenic
REVEL	0.441	indeterminate
SaProt	LLR -8.65	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 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 22 kb · p 7.7e-05 · regional, not allelic
Overall
CADD	25.9	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 0.00176% African / African-American · 1/56,949 alleles

Overall 0.000897% 1/111,536 alleles · very rare

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.Ile899Thr
Coding: c.2696T>C
MANE Select: NM_001367721
Type: single nucleotide variant
Location: chrX:41520505 (GRCh38)
Structure: AlphaFold pLDDT 79.45 · 22 PDB
Residue 899: 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; an α-helix

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

Similar variants

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
CASK p.Arg255Cys Pathogenic/Likely 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-ile899thr (accessed [today's date]).

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