Is CASK p.Ile646Val (c.1936A>G) pathogenic?

CASK p.Ile646Val (c.1936A>G) is classified Uncertain significance in CASK (ClinVar, Single submitter, 1 submitter; last evaluated 2017-05-05). AlphaMissense: likely benign (0.1557); Absent from gnomAD v4.1.

How common is CASK p.Ile646Val (c.1936A>G) in the general population?

CASK p.Ile646Val (c.1936A>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CASK p.Ile646Val (c.1936A>G)?

AlphaMissense predicts likely benign (score 0.1557) — an in-silico prediction, not a clinical call.

CASK p.Ile646Val

c.1936A>G · rs1555980007 · VCV439455

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1557 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1557	likely benign
REVEL	0.192	benign-leaning
SaProt	LLR -8.14	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 0.63, phastCons 1
Regional constraint	o/e 0.29	constrained · MANE · 11 kb · p 1.3e-08 · regional, not allelic
Overall
CADD	23.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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.Ile646Val
Coding: c.1936A>G
MANE Select: NM_001367721
dbSNP: rs1555980007
Type: single nucleotide variant
Location: chrX:41553822 (GRCh38)
Structure: AlphaFold pLDDT 79.45 · 22 PDB
Residue 646: a UniProt-annotated variant site (found in a patient with epilepsy and pontocerebellar hypoplasia; likely pathogenic); the sh3 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

Similar variants

CASK c.1015+1G>A Pathogenic ★★ same type
CASK c.1315-1G>A Pathogenic/Likely pathogenic ★★ same type
CASK c.2317+1G>A Pathogenic/Likely pathogenic ★★ same type
CASK c.2317+5G>A Pathogenic/Likely pathogenic ★★ same type
CASK c.2521-2A>G Pathogenic/Likely pathogenic ★★ same type
CASK c.59+2T>C Pathogenic/Likely pathogenic ★★ same type
CASK p.Arg106Ter Pathogenic ★★ same type
CASK p.Arg255Cys Pathogenic/Likely pathogenic ★★ same type

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-ile646val (accessed [today's date]).

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