Is CASK p.Tyr121= (c.363T>C) pathogenic?

CASK p.Tyr121= (c.363T>C) is classified Benign in CASK (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-02-03). Common (popmax 5.33%, amr) — too common for a highly-penetrant pathogenic allele; Associated with Inborn genetic diseases.

What condition is associated with CASK p.Tyr121= (c.363T>C)?

CASK p.Tyr121= (c.363T>C) is associated with Inborn genetic diseases (ClinVar).

CASK p.Tyr121=

Q: How common is CASK p.Tyr121= (c.363T>C) in the general population?

CASK p.Tyr121= (c.363T>C) is common (popmax 5.33%, amr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.363T>C · rs41431245 · VCV94378

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Common

common (popmax 5.33%, amr) — too common for a highly-penetrant pathogenic allele

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 4.5	GERP 1.2, phastCons 1
Overall
CADD	6.787	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 5.33% Admixed American · 2,429/45,589 alleles

Filtering AF 5.15% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.08%

Overall 0.41% 4,703/1,148,328 alleles · common

Ancestry group	Frequency	1 in
Admixed Americangrpmax	5.33%	19
East Asian	3.22%	31
Finnishnot grpmax-eligible	0.861%	116
Remaining individualsnot grpmax-eligible	0.634%	158
South Asian	0.252%	397
African / African-American	0.0854%	1,172
Ashkenazi Jewishnot grpmax-eligible	0.0556%	1,800
Middle Eastern	0.0483%	2,073
European (non-Finnish)	0.0363%	2,752

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.Tyr121=
Coding: c.363T>C
MANE Select: NM_001367721
dbSNP: rs41431245
Type: single nucleotide variant
Location: chrX:41739450 (GRCh38)
Structure: AlphaFold pLDDT 79.45 · 22 PDB
Residue 121: 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

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

Similar variants

CASK p.Tyr121His 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-tyr121 (accessed [today's date]).

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