Is CASK p.Asp724= (c.2172T>C) pathogenic?

CASK p.Asp724= (c.2172T>C) is classified Benign/Likely benign in CASK (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-13). Ultra-rare (popmax 0.0301%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CASK p.Asp724= (c.2172T>C)?

CASK p.Asp724= (c.2172T>C) is associated with Inborn genetic diseases (ClinVar).

How common is CASK p.Asp724= (c.2172T>C) in the general population?

CASK p.Asp724= (c.2172T>C) is ultra-rare (popmax 0.0301%, nfe) (gnomAD).

CASK p.Asp724=

c.2172T>C · rs199730401 · VCV590045

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0301%, nfe)

Conditions

Inborn genetic diseases

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 5.3	GERP -0.71, phastCons 1
Overall
CADD	8.558	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0301% European (non-Finnish) · 262/869,131 alleles

Filtering AF 0.0271% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.026%

Overall 0.0236% 278/1,179,376 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0301%	3,317
Remaining individualsnot grpmax-eligible	0.0279%	3,579
African / African-American	0.00352%	28,382
Admixed American	0.0022%	45,454

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.Asp724=
Coding: c.2172T>C
MANE Select: NM_001367721
dbSNP: rs199730401
Type: single nucleotide variant
Location: chrX:41534957 (GRCh38)
Structure: AlphaFold pLDDT 79.45 · 22 PDB
Residue 724: 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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

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
CASK p.Gly21Asp 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-asp724 (accessed [today's date]).

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