Is CASK p.Val719Met (c.2155G>A) pathogenic?

CASK p.Val719Met (c.2155G>A) is classified Likely pathogenic in CASK (ClinVar, Single submitter, 1 submitter; last evaluated 2021-12-02). AlphaMissense: likely pathogenic (0.7997); Absent from gnomAD v4.1; Associated with syndromic X-linked intellectual disability Najm type.

What condition is associated with CASK p.Val719Met (c.2155G>A)?

CASK p.Val719Met (c.2155G>A) is associated with syndromic X-linked intellectual disability Najm type (ClinVar).

How common is CASK p.Val719Met (c.2155G>A) in the general population?

CASK p.Val719Met (c.2155G>A) 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.Val719Met (c.2155G>A)?

AlphaMissense predicts likely pathogenic (score 0.7997) — an in-silico prediction, not a clinical call.

CASK p.Val719Met

c.2155G>A · rs12842195 · VCV1326849

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7997 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,162,626)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

syndromic X-linked intellectual disability Najm type

Computational evidence

Protein change
AlphaMissense	0.7997	likely pathogenic ✓ concordant with ClinVar
REVEL	0.669	pathogenic-leaning
SaProt	LLR -8.48	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	Δ0.95	donor loss · deltas
Pangolin	Δ0.69	loss · gain 0.06 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 22 kb · p 7.7e-05 · regional, not allelic
Overall
CADD	29.9	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

No allele count reported in gnomAD v4.1 (AN 1,162,626). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: CASK
Protein: p.Val719Met
Coding: c.2155G>A
MANE Select: NM_001367721
dbSNP: rs12842195
Type: single nucleotide variant
Location: chrX:41542691 (GRCh38)
Structure: AlphaFold pLDDT 79.45 · 22 PDB
Residue 719: 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

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 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
CASK p.Arg27Ter 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-val719met (accessed [today's date]).

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