Is CASK p.Arg489Trp (c.1465C>T) pathogenic?

CASK p.Arg489Trp (c.1465C>T) is classified Pathogenic/Likely pathogenic in CASK (ClinVar, Multiple submitters, 6 submitters; last evaluated 2024-04-08). AlphaMissense: likely pathogenic (0.9946); Absent from gnomAD v4.1; Associated with Smith-Magenis Syndrome-like.

What condition is associated with CASK p.Arg489Trp (c.1465C>T)?

CASK p.Arg489Trp (c.1465C>T) is associated with Smith-Magenis Syndrome-like, syndromic X-linked intellectual disability Najm type (ClinVar).

How common is CASK p.Arg489Trp (c.1465C>T) in the general population?

CASK p.Arg489Trp (c.1465C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CASK p.Arg489Trp (c.1465C>T)?

AlphaMissense predicts likely pathogenic (score 0.9946) — an in-silico prediction, not a clinical call.

CASK p.Arg489Trp

c.1465C>T · rs1114167352 · VCV254208

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.9946 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Smith-Magenis Syndrome-like

Computational evidence

Protein change
AlphaMissense	0.9946	likely pathogenic ✓ concordant with ClinVar
REVEL	0.494	indeterminate
SaProt	LLR -15.98	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP -0.31, phastCons 1
Regional constraint	o/e 0.50	unconstrained · MANE · 77 kb · p 1.9e-13 · regional, not allelic
Overall
CADD	28.5	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.Arg489Trp
Coding: c.1465C>T
MANE Select: NM_001367721
dbSNP: rs1114167352
Type: single nucleotide variant
Location: chrX:41578378 (GRCh38)
Structure: AlphaFold pLDDT 79.45 · 22 PDB
Residue 489: a UniProt-annotated variant site (found in a patient with epilepsy and pontocerebellar hypoplasia; likely pathogenic); the pdz domain; a β-strand; 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

Smith-Magenis Syndrome-like

Also linked: syndromic X-linked intellectual disability Najm type

Similar variants

CASK p.Arg489Gln Pathogenic/Likely pathogenic ★★ same residue
CASK c.1015+1G>A Pathogenic ★★ same condition
CASK c.1315-1G>A Pathogenic/Likely pathogenic ★★ same condition
CASK c.2317+1G>A Pathogenic/Likely pathogenic ★★ same condition
CASK c.2317+5G>A Pathogenic/Likely pathogenic ★★ same condition
CASK c.59+2T>C Pathogenic/Likely pathogenic ★★ same condition
CASK p.Arg106Ter Pathogenic ★★ same condition
CASK p.Arg255Cys 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-arg489trp (accessed [today's date]).

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