Is CASK p.Val913Met (c.2737G>A) pathogenic?

CASK p.Val913Met (c.2737G>A) is classified Uncertain significance in CASK (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-05-27). AlphaMissense: ambiguous (0.4419); Very rare (popmax 0.00353%, sas).

How common is CASK p.Val913Met (c.2737G>A) in the general population?

CASK p.Val913Met (c.2737G>A) is very rare (popmax 0.00353%, sas) (gnomAD).

What do computational predictors say about CASK p.Val913Met (c.2737G>A)?

AlphaMissense predicts ambiguous (score 0.4419) — an in-silico prediction, not a clinical call.

CASK p.Val913Met

c.2737G>A · rs374765049 · VCV451277

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4419 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00353%, sas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4419	ambiguous
REVEL	0.175	moderately benign-leaning
SaProt	LLR -6.35	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 7.7	GERP 1.7, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 22 kb · p 7.7e-05 · regional, not allelic
Overall
CADD	26.1	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 0.00353% South Asian · 2/56,714 alleles

Filtering AF 0.000585% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000219%

Overall 0.000414% 5/1,208,018 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00353%	28,357
Admixed American	0.00219%	45,714
African / African-American	0.00175%	57,014
European (non-Finnish)	0.000112%	893,935

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.Val913Met
Coding: c.2737G>A
MANE Select: NM_001367721
dbSNP: rs374765049
Type: single nucleotide variant
Location: chrX:41520464 (GRCh38)
Structure: AlphaFold pLDDT 79.45 · 22 PDB
Residue 913: 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

Similar variants

CASK p.Val913Leu Uncertain significance ★★ ⚠ 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-val913met (accessed [today's date]).

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