Is CASK p.Ser576Leu (c.1727C>T) pathogenic?

CASK p.Ser576Leu (c.1727C>T) is classified Uncertain significance in CASK (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-03-03). AlphaMissense: likely benign (0.0796); Absent from gnomAD v4.1; Associated with syndromic X-linked intellectual disability Najm type.

What condition is associated with CASK p.Ser576Leu (c.1727C>T)?

CASK p.Ser576Leu (c.1727C>T) is associated with syndromic X-linked intellectual disability Najm type (ClinVar).

How common is CASK p.Ser576Leu (c.1727C>T) in the general population?

CASK p.Ser576Leu (c.1727C>T) is absent from gnomAD v4.1 (gnomAD).

How is X-linked intellectual disability, Najm type inherited?

Typically X-linked dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about CASK p.Ser576Leu (c.1727C>T)?

AlphaMissense predicts likely benign (score 0.0796) — an in-silico prediction, not a clinical call.

CASK p.Ser576Leu

c.1727C>T · rs2065202221 · VCV1023129

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0796 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

syndromic X-linked intellectual disability Najm type

Computational evidence

Protein change
AlphaMissense	0.0796	likely benign
REVEL	0.187	benign-leaning
SaProt	LLR -6.64	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.30 · evaluated, not missing
Pangolin	Δ0.39	loss · gain 0.01 · SpliceAI below 0.2 · independent
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 5,911 bp · p 0.8 · regional, not allelic
Overall
CADD	23.9	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

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.Ser576Leu
Coding: c.1727C>T
MANE Select: NM_001367721
dbSNP: rs2065202221
Type: single nucleotide variant
Location: chrX:41559789 (GRCh38)
Structure: AlphaFold pLDDT 79.45 · 22 PDB
Residue 576: 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

syndromic X-linked intellectual disability Najm type — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For X-linked intellectual disability, Najm type (Orphanet):

Inheritance: X-linked dominant
Onset: Infancy, Neonatal

Similar variants

CASK p.Ser576= Likely benign ★★ 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-ser576leu (accessed [today's date]).

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