Is CASK p.Arg874His (c.2621G>A) pathogenic?

CASK p.Arg874His (c.2621G>A) is classified Uncertain significance in CASK (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-05-23). AlphaMissense: likely benign (0.2441); Very rare (popmax 0.00435%, amr); Associated with FG syndrome 4.

What condition is associated with CASK p.Arg874His (c.2621G>A)?

CASK p.Arg874His (c.2621G>A) is associated with FG syndrome 4 (ClinVar).

How common is CASK p.Arg874His (c.2621G>A) in the general population?

CASK p.Arg874His (c.2621G>A) is very rare (popmax 0.00435%, amr) (gnomAD).

What do computational predictors say about CASK p.Arg874His (c.2621G>A)?

AlphaMissense predicts likely benign (score 0.2441) — an in-silico prediction, not a clinical call.

CASK p.Arg874His

c.2621G>A · rs754713652 · VCV976216

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2441 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00435%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

FG syndrome 4

Computational evidence

Protein change
AlphaMissense	0.2441	likely benign
REVEL	0.235	benign-leaning
SaProt	LLR -10.16	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 22 kb · p 7.7e-05 · regional, not allelic
Overall
CADD	26.7	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 0.00435% Admixed American · 2/45,996 alleles

Filtering AF 0.000721% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00027%

Overall 0.000581% 7/1,204,751 alleles · very rare exomes 7/1,091,339 · genomes 0/113,412 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00435%	22,998
European (non-Finnish)	0.000562%	178,047

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.Arg874His
Coding: c.2621G>A
MANE Select: NM_001367721
dbSNP: rs754713652
Type: single nucleotide variant
Location: chrX:41520580 (GRCh38)
Structure: AlphaFold pLDDT 79.45 · 22 PDB
Residue 874: a UniProt-annotated variant site (found in a patient with epilepsy and pontocerebellar hypoplasia; likely pathogenic); the guanylate kinase-like domain; the 'required for interaction with nrxn1 (via c-terminal tail)' region; an α-helix

Full CASK gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

FG syndrome 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CASK c.2317+5G>A Pathogenic/Likely pathogenic ★★ same condition
CASK c.2521-2A>G Pathogenic/Likely pathogenic ★★ same condition
CASK c.59+2T>C Pathogenic/Likely pathogenic ★★ same condition
CASK p.Arg28Ter Pathogenic ★★ same condition
CASK p.Arg489Gln Pathogenic/Likely pathogenic ★★ same condition
CASK p.Arg613Ter Pathogenic/Likely pathogenic ★★ same condition
CASK p.Glu102Gly Pathogenic/Likely pathogenic ★★ same condition
CASK p.Tyr282Ter Pathogenic ★★ 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-arg874his (accessed [today's date]).

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