Is CASK p.Ile514Val (c.1540A>G) pathogenic?

CASK p.Ile514Val (c.1540A>G) is classified Uncertain significance in CASK (ClinVar, Single submitter, 1 submitter; last evaluated 2020-09-30). AlphaMissense: likely benign (0.0921); Very rare (popmax 0.000116%, nfe); Associated with Intellectual disability, CASK-related, X-linked.

What condition is associated with CASK p.Ile514Val (c.1540A>G)?

CASK p.Ile514Val (c.1540A>G) is associated with Intellectual disability, CASK-related, X-linked (ClinVar).

How common is CASK p.Ile514Val (c.1540A>G) in the general population?

CASK p.Ile514Val (c.1540A>G) is very rare (popmax 0.000116%, nfe) (gnomAD).

What do computational predictors say about CASK p.Ile514Val (c.1540A>G)?

AlphaMissense predicts likely benign (score 0.0921) — an in-silico prediction, not a clinical call.

CASK p.Ile514Val

c.1540A>G · rs2065378550 · VCV1016152

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0921 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000116%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Intellectual disability, CASK-related, X-linked

Computational evidence

Protein change
AlphaMissense	0.0921	likely benign
REVEL	0.205	benign-leaning
SaProt	LLR -5.35	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 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.50	unconstrained · MANE · 77 kb · p 1.9e-13 · regional, not allelic
Overall
CADD	22.3	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

Grpmax group 0.000116% European (non-Finnish) · 1/859,811 alleles

Overall 9.47e-05% 1/1,055,968 alleles · very rare

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: CASK
Protein: p.Ile514Val
Coding: c.1540A>G
MANE Select: NM_001367721
dbSNP: rs2065378550
Type: single nucleotide variant
Location: chrX:41569710 (GRCh38)
Structure: AlphaFold pLDDT 79.45 · 22 PDB
Residue 514: a UniProt-annotated variant site (found in a patient with epilepsy and pontocerebellar hypoplasia; likely pathogenic); the pdz domain; a β-strand; 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-ile514val (accessed [today's date]).

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