Is CASK p.Asp5Glu (c.15C>A) pathogenic?

CASK p.Asp5Glu (c.15C>A) is classified Uncertain significance in CASK (ClinVar, Single submitter, 1 submitter; last evaluated 2021-11-27). AlphaMissense: ambiguous (0.4223); Very rare (popmax 0.000671%, nfe); Associated with Intellectual disability, CASK-related, X-linked.

What condition is associated with CASK p.Asp5Glu (c.15C>A)?

CASK p.Asp5Glu (c.15C>A) is associated with Intellectual disability, CASK-related, X-linked (ClinVar).

How common is CASK p.Asp5Glu (c.15C>A) in the general population?

CASK p.Asp5Glu (c.15C>A) is very rare (popmax 0.000671%, nfe) (gnomAD).

What do computational predictors say about CASK p.Asp5Glu (c.15C>A)?

AlphaMissense predicts ambiguous (score 0.4223) — an in-silico prediction, not a clinical call.

CASK p.Asp5Glu

c.15C>A · rs2148116158 · VCV1395262

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4223 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000671%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Intellectual disability, CASK-related, X-linked

Computational evidence

Protein change
AlphaMissense	0.4223	ambiguous
REVEL	0.16	moderately benign-leaning
SaProt	LLR -6.24	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 11	GERP 2.8, phastCons 1
Regional constraint	o/e 0.31	constrained · MANE · 286 kb · p 1e-25 · regional, not allelic
Overall
CADD	24.3	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 0.000671% European (non-Finnish) · 6/894,602 alleles

Filtering AF 0.000241% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000547% 6/1,097,319 alleles · very rare

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.Asp5Glu
Coding: c.15C>A
MANE Select: NM_001367721
dbSNP: rs2148116158
Type: single nucleotide variant
Location: chrX:41922974 (GRCh38)
Structure: AlphaFold pLDDT 79.45 · 22 PDB

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.Asp5Asn Uncertain significance ★ ⚠ 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-asp5glu (accessed [today's date]).

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