Is CASK p.Pro324His (c.971C>A) pathogenic?

CASK p.Pro324His (c.971C>A) is classified Uncertain significance in CASK (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-26). AlphaMissense: ambiguous (0.4416); Very rare (popmax 0.000112%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CASK p.Pro324His (c.971C>A)?

CASK p.Pro324His (c.971C>A) is associated with Inborn genetic diseases (ClinVar).

How common is CASK p.Pro324His (c.971C>A) in the general population?

CASK p.Pro324His (c.971C>A) is very rare (popmax 0.000112%, nfe) (gnomAD).

What do computational predictors say about CASK p.Pro324His (c.971C>A)?

AlphaMissense predicts ambiguous (score 0.4416) — an in-silico prediction, not a clinical call.

CASK p.Pro324His

c.971C>A · VCV4605996

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4416 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000112%, nfe)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4416	ambiguous
REVEL	0.347	indeterminate
SaProt	LLR -6.33	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.50	unconstrained · MANE · 77 kb · p 1.9e-13 · regional, not allelic
Overall
CADD	24.6	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 0.000112% European (non-Finnish) · 1/891,064 alleles

Overall 8.28e-05% 1/1,207,149 alleles · very rare exomes 1/1,093,175 · genomes 0/113,974 · joint denominator

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.Pro324His
Coding: c.971C>A
MANE Select: NM_001367721
Type: single nucleotide variant
Location: chrX:41626648 (GRCh38)
Structure: AlphaFold pLDDT 79.45 · 22 PDB
Residue 324: a UniProt-annotated variant site (found in a patient with epilepsy and pontocerebellar hypoplasia; likely pathogenic)

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.Pro324= Benign ★ 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-pro324his (accessed [today's date]).

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