Is CASK p.Ser313Thr (c.937T>A) pathogenic?

CASK p.Ser313Thr (c.937T>A) is classified Conflicting classifications of pathogenicity in CASK (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-03-06). AlphaMissense: ambiguous (0.4453); Ultra-rare (popmax 0.0442%, sas); Associated with Inborn genetic diseases.

What condition is associated with CASK p.Ser313Thr (c.937T>A)?

CASK p.Ser313Thr (c.937T>A) is associated with Inborn genetic diseases (ClinVar).

How common is CASK p.Ser313Thr (c.937T>A) in the general population?

CASK p.Ser313Thr (c.937T>A) is ultra-rare (popmax 0.0442%, sas) (gnomAD).

What do computational predictors say about CASK p.Ser313Thr (c.937T>A)?

AlphaMissense predicts ambiguous (score 0.4453) — an in-silico prediction, not a clinical call.

CASK p.Ser313Thr

c.937T>A · rs755594972 · VCV589835

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4453 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0442%, sas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4453	ambiguous
REVEL	0.275	benign-leaning
SaProt	LLR -6.09	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.50	unconstrained · MANE · 77 kb · p 1.9e-13 · regional, not allelic
Overall
CADD	23.1	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 0.0442% South Asian · 25/56,510 alleles

Filtering AF 0.0307% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0262%

Overall 0.00209% 25/1,195,012 alleles · ultra-rare

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.Ser313Thr
Coding: c.937T>A
MANE Select: NM_001367721
dbSNP: rs755594972
Type: single nucleotide variant
Location: chrX:41626682 (GRCh38)
Structure: AlphaFold pLDDT 79.45 · 22 PDB
Residue 313: a modified residue (phosphoserine); a UniProt-annotated variant site (found in a patient with epilepsy and pontocerebellar hypoplasia; likely pathogenic); the 'calmodulin-binding' 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.Ser313Ter Pathogenic ★ 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-ser313thr (accessed [today's date]).

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