Is CASK p.Met507Ile (c.1521G>T) pathogenic?

CASK p.Met507Ile (c.1521G>T) is classified Uncertain significance in CASK (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-02-01). AlphaMissense: likely pathogenic (0.8074); Absent from gnomAD v4.1; Associated with Intellectual disability, CASK-related, X-linked.

What condition is associated with CASK p.Met507Ile (c.1521G>T)?

CASK p.Met507Ile (c.1521G>T) is associated with Intellectual disability, CASK-related, X-linked (ClinVar).

How common is CASK p.Met507Ile (c.1521G>T) in the general population?

CASK p.Met507Ile (c.1521G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CASK p.Met507Ile (c.1521G>T)?

AlphaMissense predicts likely pathogenic (score 0.8074) — an in-silico prediction, not a clinical call.

CASK p.Met507Ile

c.1521G>T · rs1064794341 · VCV420196

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8074 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,140,172)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Intellectual disability, CASK-related, X-linked

Computational evidence

Protein change
AlphaMissense	0.8074	likely pathogenic
REVEL	0.187	benign-leaning
SaProt	LLR -7.86	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP -0.096, phastCons 1
Regional constraint	o/e 0.50	unconstrained · MANE · 77 kb · p 1.9e-13 · regional, not allelic
Overall
CADD	24.6	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 1,140,172). 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.Met507Ile
Coding: c.1521G>T
MANE Select: NM_001367721
dbSNP: rs1064794341
Type: single nucleotide variant
Location: chrX:41569729 (GRCh38)
Structure: AlphaFold pLDDT 79.45 · 22 PDB
Residue 507: 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-met507ile (accessed [today's date]).

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