Is CASK p.Arg613Gln (c.1838G>A) pathogenic?

CASK p.Arg613Gln (c.1838G>A) is classified Likely benign in CASK (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-15). AlphaMissense: likely benign (0.3068); Very rare (popmax 0.000113%, nfe); Associated with Intellectual disability, CASK-related, X-linked.

What condition is associated with CASK p.Arg613Gln (c.1838G>A)?

CASK p.Arg613Gln (c.1838G>A) is associated with Intellectual disability, CASK-related, X-linked (ClinVar).

How common is CASK p.Arg613Gln (c.1838G>A) in the general population?

CASK p.Arg613Gln (c.1838G>A) is very rare (popmax 0.000113%, nfe) (gnomAD).

What do computational predictors say about CASK p.Arg613Gln (c.1838G>A)?

AlphaMissense predicts likely benign (score 0.3068) — an in-silico prediction, not a clinical call.

CASK p.Arg613Gln

c.1838G>A · VCV4711713

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3068 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000113%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Intellectual disability, CASK-related, X-linked

Computational evidence

Protein change
AlphaMissense	0.3068	likely benign
REVEL	0.488	indeterminate
SaProt	LLR -4.37	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL 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 1.04	unconstrained · MANE · 5,911 bp · p 0.8 · regional, not allelic
Overall
CADD	23.8	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 0.000113% European (non-Finnish) · 1/884,982 alleles

Overall 0.00025% 3/1,198,372 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00431%	23,208
European (non-Finnish)grpmax	0.000113%	884,979

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg613Gln
Coding: c.1838G>A
MANE Select: NM_001367721
Type: single nucleotide variant
Location: chrX:41555604 (GRCh38)
Structure: AlphaFold pLDDT 79.45 · 22 PDB
Residue 613: a UniProt-annotated variant site (found in a patient with epilepsy and pontocerebellar hypoplasia; likely pathogenic); the sh3 domain; 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

Intellectual disability, CASK-related, X-linked — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CASK p.Arg613Ter Pathogenic/Likely pathogenic ★★ same residue
CASK p.Arg489Gln Pathogenic/Likely pathogenic ★★ same condition
CASK p.Ala359Val Uncertain significance ★★ ⚠ same condition
CASK p.Ala833Thr Uncertain significance ★★ ⚠ same condition
CASK p.Arg130Cys Uncertain significance ★★ ⚠ same condition
CASK p.Arg572His Uncertain significance ★★ ⚠ same condition
CASK p.Arg61Trp Uncertain significance ★★ ⚠ same condition
CASK p.Asp424Gly 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-arg613gln (accessed [today's date]).

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