Is CASK p.Met519Thr (c.1556T>C) pathogenic?

CASK p.Met519Thr (c.1556T>C) is classified Uncertain significance in CASK (ClinVar, Single submitter, 1 submitter; last evaluated 2014-12-30). AlphaMissense: likely pathogenic (0.9957); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with CASK p.Met519Thr (c.1556T>C)?

CASK p.Met519Thr (c.1556T>C) is associated with Inborn genetic diseases (ClinVar).

How common is CASK p.Met519Thr (c.1556T>C) in the general population?

CASK p.Met519Thr (c.1556T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CASK p.Met519Thr (c.1556T>C)?

AlphaMissense predicts likely pathogenic (score 0.9957) — an in-silico prediction, not a clinical call.

CASK p.Met519Thr

c.1556T>C · rs1555983784 · VCV520608

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9957 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,176,128)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9957	likely pathogenic
REVEL	0.634	indeterminate
SaProt	LLR -11.87	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.50	unconstrained · MANE · 77 kb · p 1.9e-13 · regional, not allelic
Overall
CADD	24.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

No allele count reported in gnomAD v4.1 (AN 1,176,128). 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.Met519Thr
Coding: c.1556T>C
MANE Select: NM_001367721
dbSNP: rs1555983784
Type: single nucleotide variant
Location: chrX:41569694 (GRCh38)
Structure: AlphaFold pLDDT 79.45 · 22 PDB
Residue 519: 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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CASK p.Ala300Thr Uncertain significance ★★ ⚠ same condition
CASK p.Arg560Trp Uncertain significance ★★ ⚠ same condition
CASK p.Arg766Trp Uncertain significance ★★ ⚠ same condition
CASK p.Asn31Ser Uncertain significance ★★ ⚠ same condition
CASK p.Asp330Gly Uncertain significance ★★ ⚠ same condition
CASK p.Asp498Gly Uncertain significance ★★ ⚠ same condition
CASK p.Glu662Asp Uncertain significance ★★ ⚠ same condition
CASK p.Gly21Asp 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-met519thr (accessed [today's date]).

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