Is CASK p.His827= (c.2481C>T) pathogenic?

CASK p.His827= (c.2481C>T) is classified Benign/Likely benign in CASK (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-11-17). Very rare (popmax 0.00592%, eas); Associated with Intellectual disability, CASK-related, X-linked.

What condition is associated with CASK p.His827= (c.2481C>T)?

CASK p.His827= (c.2481C>T) is associated with Intellectual disability, CASK-related, X-linked (ClinVar).

How common is CASK p.His827= (c.2481C>T) in the general population?

CASK p.His827= (c.2481C>T) is very rare (popmax 0.00592%, eas) (gnomAD).

CASK p.His827=

c.2481C>T · rs775353846 · VCV1164614

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00592%, eas)

Conditions

Intellectual disability, CASK-related, X-linked

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -7.3	GERP -3.3
Overall
CADD	0.463	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00592% East Asian · 2/33,772 alleles

Filtering AF 0.00116% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000946%

Overall 0.00182% 22/1,209,938 alleles · very rare exomes 20/1,097,869 · genomes 2/112,069 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00592%	16,886
Admixed American	0.00218%	45,793
Finnishnot grpmax-eligible	0.00215%	46,573
European (non-Finnish)	0.0019%	52,649
African / African-American	0.00175%	57,235

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.His827=
Coding: c.2481C>T
MANE Select: NM_001367721
dbSNP: rs775353846
Type: single nucleotide variant
Location: chrX:41531046 (GRCh38)
Structure: AlphaFold pLDDT 79.45 · 22 PDB
Residue 827: 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

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

Similar variants

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
CASK p.Asp445Asn 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-his827 (accessed [today's date]).

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