Is CASK p.Lys297= (c.891A>G) pathogenic?

CASK p.Lys297= (c.891A>G) is classified Conflicting classifications of pathogenicity in CASK (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2025-12-19). Low-frequency (popmax 1.16%, sas); Associated with Inborn genetic diseases.

What condition is associated with CASK p.Lys297= (c.891A>G)?

CASK p.Lys297= (c.891A>G) is associated with Inborn genetic diseases (ClinVar).

How common is CASK p.Lys297= (c.891A>G) in the general population?

CASK p.Lys297= (c.891A>G) is low-frequency (popmax 1.16%, sas) (gnomAD).

CASK p.Lys297=

c.891A>G · rs544979992 · VCV166795

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.16%, sas)

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 1.1	GERP -0.58, phastCons 1
Overall
CADD	7.784	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.16% South Asian · 657/56,481 alleles

Filtering AF 1.09% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.06%

Overall 0.0635% 758/1,193,378 alleles · low-frequency

Ancestry group	Frequency	1 in
South Asiangrpmax	1.16%	86
Remaining individualsnot grpmax-eligible	0.113%	889
Middle Eastern	0.0465%	2,151
European (non-Finnish)	0.005%	19,997
Admixed American	0.00219%	45,711
African / African-American	0.00175%	57,085

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.Lys297=
Coding: c.891A>G
MANE Select: NM_001367721
dbSNP: rs544979992
Type: single nucleotide variant
Location: chrX:41636602 (GRCh38)
Structure: AlphaFold pLDDT 79.45 · 22 PDB
Residue 297: 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.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-lys297 (accessed [today's date]).

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