Is CYLD p.Asp277fs (c.831_834del) pathogenic?

CYLD p.Asp277fs (c.831834del) is classified Pathogenic in CYLD (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-11-25). Very rare (popmax 8.48e-05%, nfe); Associated with familial cylindromatosis.

What condition is associated with CYLD p.Asp277fs (c.831_834del)?

CYLD p.Asp277fs (c.831_834del) is associated with familial cylindromatosis (ClinVar).

How common is CYLD p.Asp277fs (c.831_834del) in the general population?

CYLD p.Asp277fs (c.831_834del) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

How is Brooke-Spiegler syndrome inherited?

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

CYLD p.Asp277fs

c.831_834del · rs886040868 · VCV267228

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Conditions

familial cylindromatosis

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 5 of 19
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 12	GERP 2.4, phastCons 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,178,642 alleles

Overall 6.85e-05% 1/1,460,088 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: CYLD
Protein: p.Asp277fs
Coding: c.831_834del
MANE Select: NM_001378743
dbSNP: rs886040868
Type: Deletion
Location: chr16:50754339 (GRCh38)
Gene constraint: LOEUF 0.325 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.06 · 6 PDB
Residue 277: the cap-gly 2 domain; the 'interaction with trip' region

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

Disease context

familial cylindromatosis — 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.Lys764fs Pathogenic ★★ same condition
CYLD c.1950-2_1953del Pathogenic ★ same condition
CYLD p.Asn553fs Pathogenic ★ same condition
CYLD p.Cys802_Tyr803delinsTer Pathogenic ★ same condition
CYLD p.Ser839fs Pathogenic ★ same condition
CYLD p.Asp277Asn Uncertain significance ★ ⚠ same residue
CYLD c.1950-1_1952del Pathogenic same condition
CYLD p.Arg758Ter 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/cyld-p-asp277fs (accessed [today's date]).

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