Is CYLD p.Ile491= (c.1473C>T) pathogenic?

CYLD p.Ile491= (c.1473C>T) is classified Benign/Likely benign in CYLD (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-05-12). Low-frequency (popmax 2.58%, afr); Associated with familial multiple trichoepithelioma.

What condition is associated with CYLD p.Ile491= (c.1473C>T)?

CYLD p.Ile491= (c.1473C>T) is associated with familial multiple trichoepithelioma, familial cylindromatosis, Brooke-Spiegler syndrome (ClinVar).

How common is CYLD p.Ile491= (c.1473C>T) in the general population?

CYLD p.Ile491= (c.1473C>T) is low-frequency (popmax 2.58%, afr) (gnomAD).

How is Brooke-Spiegler syndrome inherited?

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

CYLD p.Ile491=

c.1473C>T · rs75757530 · VCV319503

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

low-frequency (popmax 2.58%, afr)

Conditions

familial multiple trichoepithelioma

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 -1.7	GERP -3.9
Overall
CADD	5.297	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 2.58% African / African-American · 1,935/75,038 alleles

Filtering AF 2.48% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.44%

Overall 0.139% 2,238/1,614,114 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	2.58%	39
Admixed American	0.218%	458
Remaining individualsnot grpmax-eligible	0.174%	573
Middle Eastern	0.149%	673
East Asian	0.00669%	14,959
South Asian	0.00659%	15,179
European (non-Finnish)	0.00381%	26,222

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.Ile491=
Coding: c.1473C>T
MANE Select: NM_001378743
dbSNP: rs75757530
Type: single nucleotide variant
Location: chr16:50779999 (GRCh38)
Gene constraint: LOEUF 0.325 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.06 · 6 PDB
Residue 491: the 'interaction with trip' region; a β-strand; the 'interaction with ikbkg/nemo' region

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

Also linked: familial cylindromatosis Brooke-Spiegler syndrome trichoepithelioma, multiple familial, 1

For Brooke-Spiegler syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult

Similar variants

CYLD p.Arg758Ter Pathogenic ★★ same condition
CYLD p.Arg936Ter Pathogenic/Likely pathogenic ★★ same condition
CYLD p.Lys767Ter Pathogenic ★★ same condition
CYLD p.Ser371Ter Pathogenic ★★ same condition
CYLD c.*3229C>T Uncertain significance ★★ same condition
CYLD p.Gly593Asp Uncertain significance ★★ ⚠ same condition
CYLD p.Thr389Arg Uncertain significance ★★ ⚠ same condition
CYLD c.2109-10G>A 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-ile491 (accessed [today's date]).

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