Is CASK p.Asn540Ser (c.1619A>G) pathogenic?

CASK p.Asn540Ser (c.1619A>G) is classified Conflicting classifications of pathogenicity in CASK (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-12-01). AlphaMissense: ambiguous (0.4075); Very rare (popmax 0.00124%, nfe); Associated with Intellectual disability, CASK-related, X-linked.

What condition is associated with CASK p.Asn540Ser (c.1619A>G)?

CASK p.Asn540Ser (c.1619A>G) is associated with Intellectual disability, CASK-related, X-linked (ClinVar).

How common is CASK p.Asn540Ser (c.1619A>G) in the general population?

CASK p.Asn540Ser (c.1619A>G) is very rare (popmax 0.00124%, nfe) (gnomAD).

What do computational predictors say about CASK p.Asn540Ser (c.1619A>G)?

AlphaMissense predicts ambiguous (score 0.4075) — an in-silico prediction, not a clinical call.

CASK p.Asn540Ser

c.1619A>G · rs1297266241 · VCV2900480

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4075 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00124%, nfe)

Conditions

Intellectual disability, CASK-related, X-linked

Computational evidence

Protein change
AlphaMissense	0.4075	ambiguous
REVEL	0.623	indeterminate
SaProt	LLR -14.42	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 1.9, phastCons 1
Regional constraint	o/e 0.50	unconstrained · MANE · 77 kb · p 1.9e-13 · regional, not allelic
Overall
CADD	26.1	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 0.00124% European (non-Finnish) · 11/888,548 alleles

Filtering AF 0.000664% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000485%

Overall 0.000998% 12/1,202,717 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00211%	47,352
European (non-Finnish)grpmax	0.00124%	80,777

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Asn540Ser
Coding: c.1619A>G
MANE Select: NM_001367721
dbSNP: rs1297266241
Type: single nucleotide variant
Location: chrX:41561608 (GRCh38)
Structure: AlphaFold pLDDT 79.45 · 22 PDB
Residue 540: a UniProt-annotated variant site (found in a patient with epilepsy and pontocerebellar hypoplasia; likely pathogenic); the pdz domain; 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

Intellectual disability, CASK-related, X-linked — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

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
CASK p.Asp424Gly Uncertain significance ★★ ⚠ same condition
CASK p.Asp445Asn 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-asn540ser (accessed [today's date]).

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