Is CASK p.Ser602Leu (c.1805C>T) pathogenic?

CASK p.Ser602Leu (c.1805C>T) is classified Uncertain significance in CASK (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-01-20). AlphaMissense: likely benign (0.0574); Very rare (popmax 0.00437%, amr); Associated with Intellectual disability, CASK-related, X-linked.

What condition is associated with CASK p.Ser602Leu (c.1805C>T)?

CASK p.Ser602Leu (c.1805C>T) is associated with Intellectual disability, CASK-related, X-linked (ClinVar).

How common is CASK p.Ser602Leu (c.1805C>T) in the general population?

CASK p.Ser602Leu (c.1805C>T) is very rare (popmax 0.00437%, amr) (gnomAD).

What do computational predictors say about CASK p.Ser602Leu (c.1805C>T)?

AlphaMissense predicts likely benign (score 0.0574) — an in-silico prediction, not a clinical call.

CASK p.Ser602Leu

c.1805C>T · rs868537608 · VCV1308035

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0574 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00437%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Intellectual disability, CASK-related, X-linked

Computational evidence

Protein change
AlphaMissense	0.0574	likely benign
REVEL	0.197	benign-leaning
SaProt	LLR -8.33	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 5,911 bp · p 0.8 · regional, not allelic
Overall
CADD	21.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00437% Admixed American · 2/45,727 alleles

Filtering AF 0.000725% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000271%

Overall 0.000415% 5/1,204,749 alleles · very rare exomes 3/1,092,854 · genomes 2/111,895 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00437%	22,864
Remaining individualsnot grpmax-eligible	0.00211%	47,431
European (non-Finnish)	0.000225%	445,228

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.Ser602Leu
Coding: c.1805C>T
MANE Select: NM_001367721
dbSNP: rs868537608
Type: single nucleotide variant
Location: chrX:41557033 (GRCh38)
Structure: AlphaFold pLDDT 79.45 · 22 PDB
Residue 602: a UniProt-annotated variant site (found in a patient with epilepsy and pontocerebellar hypoplasia; likely pathogenic); the 'required for interaction with nrxn1 (via c-terminal tail)' region; the 'disordered' 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.Ser602= Uncertain significance ★ same residue
CASK p.Ser602Ala 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

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-ser602leu (accessed [today's date]).

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