Is CASK p.Ser155Leu (c.464C>T) pathogenic?

CASK p.Ser155Leu (c.464C>T) is classified Likely pathogenic in CASK (ClinVar, Single submitter, 2 submitters; last evaluated 2023-07-16). AlphaMissense: likely pathogenic (0.9944); Very rare (popmax 0.000112%, nfe); Associated with FG syndrome 4.

What condition is associated with CASK p.Ser155Leu (c.464C>T)?

CASK p.Ser155Leu (c.464C>T) is associated with FG syndrome 4 (ClinVar).

How common is CASK p.Ser155Leu (c.464C>T) in the general population?

CASK p.Ser155Leu (c.464C>T) is very rare (popmax 0.000112%, nfe) (gnomAD).

What do computational predictors say about CASK p.Ser155Leu (c.464C>T)?

AlphaMissense predicts likely pathogenic (score 0.9944) — an in-silico prediction, not a clinical call.

CASK p.Ser155Leu

c.464C>T · rs2519234687 · VCV3254723

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9944 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000112%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

FG syndrome 4

Computational evidence

Protein change
AlphaMissense	0.9944	likely pathogenic ✓ concordant with ClinVar
REVEL	0.552	indeterminate
SaProt	LLR -13.40	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.47 · evaluated, not missing
Constraint at this position
Conservation	phyloP 9.9	GERP 1.7, phastCons 1
Regional constraint	o/e 0.31	constrained · MANE · 286 kb · p 1e-25 · regional, not allelic
Overall
CADD	29.1	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 0.000112% European (non-Finnish) · 1/891,048 alleles

Overall 9.15e-05% 1/1,093,284 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.Ser155Leu
Coding: c.464C>T
MANE Select: NM_001367721
dbSNP: rs2519234687
Type: single nucleotide variant
Location: chrX:41671496 (GRCh38)
Structure: AlphaFold pLDDT 79.45 · 22 PDB
Residue 155: the protein kinase domain; a modified residue (phosphoserine; by autocatalysis); 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.Ser155= Benign/Likely benign ★★ 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-ser155leu (accessed [today's date]).

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