Is CYLD p.Pro453fs (c.1356dup) pathogenic?

CYLD p.Pro453fs (c.1356dup) is classified Likely pathogenic in CYLD (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-28). Associated with CYLD-related disorder.

What condition is associated with CYLD p.Pro453fs (c.1356dup)?

CYLD p.Pro453fs (c.1356dup) is associated with CYLD-related disorder (ClinVar).

CYLD p.Pro453fs

c.1356dup · VCV4929852

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

Conditions

CYLD-related disorder

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 9 of 19
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 4	GERP 1.3, phastCons 0.33

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

Variant & gene context

Gene: CYLD
Protein: p.Pro453fs
Coding: c.1356dup
MANE Select: NM_001378743
Type: Duplication
Location: chr16:50779881 (GRCh38)
Gene constraint: LOEUF 0.325 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.06 · 6 PDB
Residue 453: the 'interaction with trip' region; the 'interaction with traf2' region

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

Disease context

CYLD-related disorder

Similar variants

CYLD p.Asn559Ter Pathogenic ★ same condition
CYLD p.Asp762fs Pathogenic ★ same condition
CYLD p.Thr389fs Pathogenic ★ same condition
CYLD p.Pro453Arg Uncertain significance ★ ⚠ same residue
CYLD p.Pro453Thr Uncertain significance ★ ⚠ same residue
CYLD c.1139-3dup Likely benign same condition
CYLD p.Arg235Ter Pathogenic/Likely 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-pro453fs (accessed [today's date]).

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