Is CYLD p.Glu747fs (c.2240_2241del) pathogenic?

CYLD p.Glu747fs (c.22402241del) is classified Pathogenic in CYLD (ClinVar, No assertion criteria, 1 submitter; last evaluated 2005-12-01). Absent from gnomAD; Associated with familial multiple trichoepithelioma.

What condition is associated with CYLD p.Glu747fs (c.2240_2241del)?

CYLD p.Glu747fs (c.2240_2241del) is associated with familial multiple trichoepithelioma (ClinVar).

How common is CYLD p.Glu747fs (c.2240_2241del) in the general population?

CYLD p.Glu747fs (c.2240_2241del) is absent from gnomAD (gnomAD).

How is Brooke-Spiegler syndrome inherited?

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

CYLD p.Glu747fs

c.2240_2241del · rs1597085967 · VCV5256

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Not reported

no gnomAD frequency available for this variant

Conditions

familial multiple trichoepithelioma

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 15 of 19
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 5.9	GERP 2, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

dbSNP / gnomAD

No gnomAD frequency available for this variant. This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: CYLD
Protein: p.Glu747fs
Coding: c.2240_2241del
MANE Select: NM_001378743
dbSNP: rs1597085967
Type: Microsatellite
Location: chr16:50791687 (GRCh38)
Gene constraint: LOEUF 0.325 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.06 · 6 PDB
Residue 747: a β-strand; a UniProt-annotated variant site (in mft1 and brss); the usp domain

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

Disease context

familial multiple trichoepithelioma — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Brooke-Spiegler syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult

Similar variants

CYLD p.Glu747Gly Pathogenic same residue
CYLD p.Glu747= Uncertain significance ★ same residue
CYLD p.Arg936Ter Pathogenic/Likely pathogenic ★★ same condition
CYLD c.1950-5_1950-2del Uncertain significance ★★ same condition
CYLD c.*3229C>T Uncertain significance ★★ same condition
CYLD p.Thr389Arg Uncertain significance ★★ ⚠ same condition
CYLD c.2109-10G>A Benign ★★ same condition
CYLD c.2469+10C>T Benign/Likely benign ★★ 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/cyld-p-glu747fs (accessed [today's date]).

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