Is CASK p.Leu912Phe (c.2734C>T) pathogenic?

CASK p.Leu912Phe (c.2734C>T) is classified Uncertain significance in CASK (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-05-20). AlphaMissense: likely benign (0.1169); Very rare (popmax 0.00879%, sas); Associated with syndromic X-linked intellectual disability Najm type.

What condition is associated with CASK p.Leu912Phe (c.2734C>T)?

CASK p.Leu912Phe (c.2734C>T) is associated with syndromic X-linked intellectual disability Najm type, FG syndrome 4 (ClinVar).

How common is CASK p.Leu912Phe (c.2734C>T) in the general population?

CASK p.Leu912Phe (c.2734C>T) is very rare (popmax 0.00879%, sas) (gnomAD).

How is X-linked intellectual disability, Najm type inherited?

Typically X-linked dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about CASK p.Leu912Phe (c.2734C>T)?

AlphaMissense predicts likely benign (score 0.1169) — an in-silico prediction, not a clinical call.

CASK p.Leu912Phe

c.2734C>T · rs777220099 · VCV658905

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1169 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00879%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

syndromic X-linked intellectual disability Najm type

Computational evidence

Protein change
AlphaMissense	0.1169	likely benign
REVEL	0.091	moderately benign-leaning
SaProt	LLR -8.62	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.38 · evaluated, not missing
Constraint at this position
Conservation	phyloP 9.9	GERP 1.7, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 22 kb · p 7.7e-05 · regional, not allelic
Overall
CADD	23.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00879% South Asian · 5/56,888 alleles

Filtering AF 0.0034% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00216%

Overall 0.00219% 24/1,096,274 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00879%	11,378
European (non-Finnish)	0.00213%	47,055

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.Leu912Phe
Coding: c.2734C>T
MANE Select: NM_001367721
dbSNP: rs777220099
Type: single nucleotide variant
Location: chrX:41520467 (GRCh38)
Structure: AlphaFold pLDDT 79.45 · 22 PDB
Residue 912: a UniProt-annotated variant site (found in a patient with epilepsy and pontocerebellar hypoplasia; likely pathogenic); an α-helix

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

Disease context

syndromic X-linked intellectual disability Najm type — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: FG syndrome 4

For X-linked intellectual disability, Najm type (Orphanet):

Inheritance: X-linked dominant
Onset: Infancy, Neonatal

Similar variants

CASK c.1015+1G>A Pathogenic ★★ same condition
CASK c.1315-1G>A Pathogenic/Likely pathogenic ★★ same condition
CASK c.2317+1G>A Pathogenic/Likely pathogenic ★★ same condition
CASK c.2317+5G>A Pathogenic/Likely pathogenic ★★ same condition
CASK c.2521-2A>G Pathogenic/Likely pathogenic ★★ same condition
CASK c.59+2T>C Pathogenic/Likely pathogenic ★★ same condition
CASK p.Arg106Ter Pathogenic ★★ same condition
CASK p.Arg255Cys Pathogenic/Likely 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-p-leu912phe (accessed [today's date]).

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