Is CASK p.Arg572Cys (c.1714C>T) pathogenic?

CASK p.Arg572Cys (c.1714C>T) is classified Conflicting classifications of pathogenicity in CASK (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-11-03). AlphaMissense: likely benign (0.3183); Very rare (popmax 0.00524%, afr); Associated with FG syndrome 4.

What condition is associated with CASK p.Arg572Cys (c.1714C>T)?

CASK p.Arg572Cys (c.1714C>T) is associated with FG syndrome 4 (ClinVar).

How common is CASK p.Arg572Cys (c.1714C>T) in the general population?

CASK p.Arg572Cys (c.1714C>T) is very rare (popmax 0.00524%, afr) (gnomAD).

What do computational predictors say about CASK p.Arg572Cys (c.1714C>T)?

AlphaMissense predicts likely benign (score 0.3183) — an in-silico prediction, not a clinical call.

CASK p.Arg572Cys

c.1714C>T · rs1421702106 · VCV948190

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.3183 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00524%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

FG syndrome 4

Computational evidence

Protein change
AlphaMissense	0.3183	likely benign
REVEL	0.462	indeterminate
SaProt	LLR -11.20	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
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 1.04	unconstrained · MANE · 5,911 bp · p 0.8 · regional, not allelic
Overall
CADD	31.0	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 0.00524% African / African-American · 3/57,271 alleles

Filtering AF 0.00139% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000685%

Overall 0.000414% 5/1,208,815 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00524%	19,090
European (non-Finnish)	0.000224%	447,039

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.Arg572Cys
Coding: c.1714C>T
MANE Select: NM_001367721
dbSNP: rs1421702106
Type: single nucleotide variant
Location: chrX:41559802 (GRCh38)
Structure: AlphaFold pLDDT 79.45 · 22 PDB
Residue 572: a UniProt-annotated variant site (found in a patient with epilepsy and pontocerebellar hypoplasia; likely pathogenic); the 'required for interaction with nrxn1 (via c-terminal tail)' region

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 p.Arg572His Uncertain significance ★★ ⚠ same residue
CASK p.Arg572Pro Uncertain significance ★ same residue
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

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-arg572cys (accessed [today's date]).

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