Is CASK p.Pro144= (c.432C>T) pathogenic?

CASK p.Pro144= (c.432C>T) is classified Benign/Likely benign in CASK (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-03). Ultra-rare (popmax 0.0571%, amr); Associated with Intellectual disability, CASK-related, X-linked.

What condition is associated with CASK p.Pro144= (c.432C>T)?

CASK p.Pro144= (c.432C>T) is associated with Intellectual disability, CASK-related, X-linked (ClinVar).

How common is CASK p.Pro144= (c.432C>T) in the general population?

CASK p.Pro144= (c.432C>T) is ultra-rare (popmax 0.0571%, amr) (gnomAD).

CASK p.Pro144=

c.432C>T · rs761142771 · VCV771584

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0571%, amr)

Conditions

Intellectual disability, CASK-related, X-linked

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.3	GERP -0.53, phastCons 1
Overall
CADD	13.82	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0571% Admixed American · 26/45,518 alleles

Filtering AF 0.04% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0343%

Overall 0.00815% 95/1,165,329 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0571%	1,751
Remaining individualsnot grpmax-eligible	0.0108%	9,241
European (non-Finnish)	0.00736%	13,580
African / African-American	0.00179%	55,846

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.Pro144=
Coding: c.432C>T
MANE Select: NM_001367721
dbSNP: rs761142771
Type: single nucleotide variant
Location: chrX:41671528 (GRCh38)
Structure: AlphaFold pLDDT 79.45 · 22 PDB
Residue 144: the protein kinase domain; a UniProt-annotated variant site (found in a patient with epilepsy and pontocerebellar hypoplasia; likely pathogenic); an α-helix

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.Pro144Ser Uncertain significance ★ ⚠ same residue
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

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-pro144 (accessed [today's date]).

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