Is CASK p.Pro329Thr (c.985C>A) pathogenic?

CASK p.Pro329Thr (c.985C>A) is classified Uncertain significance in CASK (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-01). AlphaMissense: likely benign (0.0813); Ultra-rare (popmax 0.0124%, sas).

How common is CASK p.Pro329Thr (c.985C>A) in the general population?

CASK p.Pro329Thr (c.985C>A) is ultra-rare (popmax 0.0124%, sas) (gnomAD).

What do computational predictors say about CASK p.Pro329Thr (c.985C>A)?

AlphaMissense predicts likely benign (score 0.0813) — an in-silico prediction, not a clinical call.

CASK p.Pro329Thr

c.985C>A · rs771426240 · VCV810579

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0813 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0124%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0813	likely benign
REVEL	0.107	moderately benign-leaning
SaProt	LLR -6.49	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 0.98, phastCons 1
Regional constraint	o/e 0.50	unconstrained · MANE · 77 kb · p 1.9e-13 · regional, not allelic
Overall
CADD	22.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0124% South Asian · 7/56,659 alleles

Filtering AF 0.00572% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00409%

Overall 0.000918% 10/1,089,421 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0124%	8,094
European (non-Finnish)	0.000338%	295,827

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.Pro329Thr
Coding: c.985C>A
MANE Select: NM_001367721
dbSNP: rs771426240
Type: single nucleotide variant
Location: chrX:41626634 (GRCh38)
Structure: AlphaFold pLDDT 79.45 · 22 PDB
Residue 329: 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

Similar variants

CASK p.Pro329fs Likely pathogenic ★ same residue
CASK c.1015+1G>A Pathogenic ★★ same type
CASK c.1315-1G>A Pathogenic/Likely pathogenic ★★ same type
CASK c.2317+1G>A Pathogenic/Likely pathogenic ★★ same type
CASK c.2317+5G>A Pathogenic/Likely pathogenic ★★ same type
CASK c.2521-2A>G Pathogenic/Likely pathogenic ★★ same type
CASK c.59+2T>C Pathogenic/Likely pathogenic ★★ same type
CASK p.Arg106Ter Pathogenic ★★ same type

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-pro329thr (accessed [today's date]).

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