Is CASK p.Leu725= (c.2175T>C) pathogenic?

CASK p.Leu725= (c.2175T>C) is classified Benign/Likely benign in CASK (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-07-23). Ultra-rare (popmax 0.0395%, amr); Associated with Inborn genetic diseases.

What condition is associated with CASK p.Leu725= (c.2175T>C)?

CASK p.Leu725= (c.2175T>C) is associated with Inborn genetic diseases (ClinVar).

How common is CASK p.Leu725= (c.2175T>C) in the general population?

CASK p.Leu725= (c.2175T>C) is ultra-rare (popmax 0.0395%, amr) (gnomAD).

CASK p.Leu725=

c.2175T>C · rs757563548 · VCV470209

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0395%, amr)

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 4.7	GERP 1.7, phastCons 1
Overall
CADD	8.209	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0395% Admixed American · 18/45,570 alleles

Filtering AF 0.0255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.021%

Overall 0.00261% 31/1,186,093 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0395%	2,532
African / African-American	0.0105%	9,494
Remaining individualsnot grpmax-eligible	0.00856%	11,684
European (non-Finnish)	0.000343%	291,538

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.Leu725=
Coding: c.2175T>C
MANE Select: NM_001367721
dbSNP: rs757563548
Type: single nucleotide variant
Location: chrX:41534954 (GRCh38)
Structure: AlphaFold pLDDT 79.45 · 22 PDB
Residue 725: 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.Leu725Pro Uncertain significance ★ ⚠ same residue
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

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-leu725 (accessed [today's date]).

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