Is CASK p.Phe163Leu (c.487T>C) pathogenic?

CASK p.Phe163Leu (c.487T>C) is classified Likely pathogenic in CASK (ClinVar, Single submitter, 1 submitter). AlphaMissense: likely pathogenic (0.9993); Absent from gnomAD v4.1; Associated with intellectual disability.

What condition is associated with CASK p.Phe163Leu (c.487T>C)?

CASK p.Phe163Leu (c.487T>C) is associated with intellectual disability (ClinVar).

How common is CASK p.Phe163Leu (c.487T>C) in the general population?

CASK p.Phe163Leu (c.487T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CASK p.Phe163Leu (c.487T>C)?

AlphaMissense predicts likely pathogenic (score 0.9993) — an in-silico prediction, not a clinical call.

CASK p.Phe163Leu

c.487T>C · rs2147495667 · VCV1172654

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9993 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

intellectual disability

Computational evidence

Protein change
AlphaMissense	0.9993	likely pathogenic ✓ concordant with ClinVar · top 4% in CASK
REVEL	0.872	moderately pathogenic-leaning
SaProt	LLR -12.11	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.7, phastCons 1
Regional constraint	o/e 0.31	constrained · MANE · 286 kb · p 1e-25 · regional, not allelic
Overall
CADD	26.8	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.Phe163Leu
Coding: c.487T>C
MANE Select: NM_001367721
dbSNP: rs2147495667
Type: single nucleotide variant
Location: chrX:41671473 (GRCh38)
Structure: AlphaFold pLDDT 79.45 · 22 PDB
Residue 163: the protein kinase domain; a UniProt-annotated variant site (found in a patient with epilepsy and pontocerebellar hypoplasia; likely pathogenic); an α-helix

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

Disease context

intellectual disability — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CASK p.Arg639Ter Pathogenic ★★ same condition
CASK p.Gly164Arg Likely pathogenic ★ same condition
CASK p.Asp794Val Uncertain significance ★ ⚠ same condition
CASK p.Gly206Ser Conflicting classifications of pathogenicity ★ ⚠ same condition
CASK p.Met501Val Uncertain significance ★ ⚠ same condition
CASK p.Ala342Val Uncertain significance ⚠ same condition
CASK p.Val292del Likely pathogenic ★★ same condition
CASK c.1015+1G>A 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-phe163leu (accessed [today's date]).

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