Is CASK p.Phe375= (c.1125C>T) pathogenic?

CASK p.Phe375= (c.1125C>T) is classified Benign/Likely benign in CASK (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-02-03). Low-frequency (popmax 1.33%, afr); Associated with Inborn genetic diseases.

What condition is associated with CASK p.Phe375= (c.1125C>T)?

CASK p.Phe375= (c.1125C>T) is associated with Inborn genetic diseases (ClinVar).

How common is CASK p.Phe375= (c.1125C>T) in the general population?

CASK p.Phe375= (c.1125C>T) is low-frequency (popmax 1.33%, afr) (gnomAD).

CASK p.Phe375=

c.1125C>T · rs141790702 · VCV210580

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.33%, afr)

Conditions

Inborn genetic diseases

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 12	GERP 1.2, phastCons 1
Overall
CADD	12.79	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.33% African / African-American · 763/57,210 alleles

Filtering AF 1.26% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.22%

Overall 0.071% 857/1,206,750 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.33%	75
Remaining individualsnot grpmax-eligible	0.0947%	1,056
Admixed American	0.0831%	1,204
Middle Eastern	0.046%	2,173
European (non-Finnish)	0.00101%	99,133

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.Phe375=
Coding: c.1125C>T
MANE Select: NM_001367721
dbSNP: rs141790702
Type: single nucleotide variant
Location: chrX:41609934 (GRCh38)
Structure: AlphaFold pLDDT 79.45 · 22 PDB
Residue 375: the l27 1 domain; a UniProt-annotated variant site (found in a patient with epilepsy and pontocerebellar hypoplasia; likely pathogenic)

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CASK p.Ala300Thr Uncertain significance ★★ ⚠ same condition
CASK p.Arg560Trp Uncertain significance ★★ ⚠ same condition
CASK p.Arg766Trp Uncertain significance ★★ ⚠ same condition
CASK p.Asn31Ser Uncertain significance ★★ ⚠ same condition
CASK p.Asp330Gly Uncertain significance ★★ ⚠ same condition
CASK p.Asp498Gly Uncertain significance ★★ ⚠ same condition
CASK p.Glu662Asp Uncertain significance ★★ ⚠ same condition
CASK p.Gly21Asp 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-phe375 (accessed [today's date]).

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