Is CASK p.Thr573Ile (c.1718C>T) pathogenic?

CASK p.Thr573Ile (c.1718C>T) is classified Conflicting classifications of pathogenicity in CASK (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-01-19). AlphaMissense: likely benign (0.172); Ultra-rare (popmax 0.0187%, nfe); Associated with Intellectual disability, CASK-related, X-linked.

What condition is associated with CASK p.Thr573Ile (c.1718C>T)?

CASK p.Thr573Ile (c.1718C>T) is associated with Intellectual disability, CASK-related, X-linked (ClinVar).

How common is CASK p.Thr573Ile (c.1718C>T) in the general population?

CASK p.Thr573Ile (c.1718C>T) is ultra-rare (popmax 0.0187%, nfe) (gnomAD).

What do computational predictors say about CASK p.Thr573Ile (c.1718C>T)?

AlphaMissense predicts likely benign (score 0.172) — an in-silico prediction, not a clinical call.

CASK p.Thr573Ile

c.1718C>T · rs141840001 · VCV194841

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.172 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0187%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Intellectual disability, CASK-related, X-linked

Computational evidence

Protein change
AlphaMissense	0.172	likely benign
REVEL	0.208	benign-leaning
SaProt	LLR -9.12	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 9.9	GERP 1.9, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 5,911 bp · p 0.8 · regional, not allelic
Overall
CADD	23.7	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0187% European (non-Finnish) · 167/894,181 alleles

Filtering AF 0.0164% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0154%

Overall 0.0145% 175/1,209,115 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0187%	5,354
Remaining individualsnot grpmax-eligible	0.00841%	11,887
South Asian	0.00353%	28,329
Finnishnot grpmax-eligible	0.00214%	46,672
African / African-American	0.00174%	57,319

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.Thr573Ile
Coding: c.1718C>T
MANE Select: NM_001367721
dbSNP: rs141840001
Type: single nucleotide variant
Location: chrX:41559798 (GRCh38)
Structure: AlphaFold pLDDT 79.45 · 22 PDB
Residue 573: a UniProt-annotated variant site (found in a patient with epilepsy and pontocerebellar hypoplasia; likely pathogenic); 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.Thr573Ser Conflicting classifications of pathogenicity ★ ⚠ 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-thr573ile (accessed [today's date]).

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