Is CASK c.2155+4G>A pathogenic?

CASK c.2155+4G>A is classified Conflicting classifications of pathogenicity in CASK (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-01-06). Very rare (popmax 0.000601%, nfe); Associated with CASK-related disorder.

What condition is associated with CASK c.2155+4G>A?

CASK c.2155+4G>A is associated with CASK-related disorder (ClinVar).

How common is CASK c.2155+4G>A in the general population?

CASK c.2155+4G>A is very rare (popmax 0.000601%, nfe) (gnomAD).

CASK c.2155+4G>A

rs749155089 · VCV537751

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.000601%, nfe)

Conditions

CASK-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
Splice region	donor +4	donor splice region (+4, within the first 6 intronic nt) · inside the BP7-excluded zone
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.89	GERP 1.9, phastCons 1
Non-coding constraint	—	not assessed · autosomes only, so chrX has no window · absence ≠ unconstrained
Overall
CADD	16.21	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000601% European (non-Finnish) · 5/832,306 alleles

Filtering AF 0.000176% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000128%

Overall 0.000701% 8/1,140,780 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00463%	21,593
Remaining individualsnot grpmax-eligible	0.00442%	22,631
European (non-Finnish)grpmax	0.000601%	166,461

Ashkenazi Jewish 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
Coding: c.2155+4G>A
MANE Select: NM_001367721
dbSNP: rs749155089
Type: single nucleotide variant
Location: chrX:41542687 (GRCh38)
Structure: AlphaFold pLDDT 79.45 · 22 PDB

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

Disease context

CASK-related disorder

Similar variants

CASK p.Arg28Ter Pathogenic ★★ same condition
CASK p.Arg489Trp Pathogenic/Likely pathogenic ★★ same condition
CASK p.Gln494Ter Pathogenic/Likely pathogenic ★★ same condition
CASK c.1668+5G>A Likely pathogenic ★ same condition
CASK c.1737+2T>A Pathogenic ★ same condition
CASK c.708+2T>G Pathogenic ★ same condition
CASK c.709-1G>A Likely pathogenic ★ same condition
CASK p.Gln527Ter 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-c-2155-plus-4g-a (accessed [today's date]).

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