Is CASK p.Phe767Cys (c.2300T>G) pathogenic?

CASK p.Phe767Cys (c.2300T>G) is classified Uncertain significance in CASK (ClinVar, Single submitter, 2 submitters; last evaluated 2024-10-07). AlphaMissense: likely pathogenic (0.9917); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with CASK p.Phe767Cys (c.2300T>G)?

CASK p.Phe767Cys (c.2300T>G) is associated with Inborn genetic diseases (ClinVar).

How common is CASK p.Phe767Cys (c.2300T>G) in the general population?

CASK p.Phe767Cys (c.2300T>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CASK p.Phe767Cys (c.2300T>G)?

AlphaMissense predicts likely pathogenic (score 0.9917) — an in-silico prediction, not a clinical call.

CASK p.Phe767Cys

c.2300T>G · VCV3485096

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9917 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9917	likely pathogenic
REVEL	0.77	pathogenic-leaning
SaProt	LLR -12.66	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>T here scores Δ0.65 · evaluated, not missing
Constraint at this position
Conservation	phyloP 11	GERP 1.5, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 22 kb · p 7.7e-05 · regional, not allelic
Overall
CADD	31.0	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

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.Phe767Cys
Coding: c.2300T>G
MANE Select: NM_001367721
Type: single nucleotide variant
Location: chrX:41534723 (GRCh38)
Structure: AlphaFold pLDDT 79.45 · 22 PDB
Residue 767: a UniProt-annotated variant site (found in a patient with epilepsy and pontocerebellar hypoplasia; likely pathogenic); the guanylate kinase-like 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.Phe767Leu Uncertain significance ★ ⚠ same residue
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

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-phe767cys (accessed [today's date]).

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