Is CYLD p.Leu773= (c.2319G>A) pathogenic?

CYLD p.Leu773= (c.2319G>A) is classified Benign/Likely benign in CYLD (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-12-09). Rare (popmax 0.396%, eas); Associated with familial multiple trichoepithelioma.

What condition is associated with CYLD p.Leu773= (c.2319G>A)?

CYLD p.Leu773= (c.2319G>A) is associated with familial multiple trichoepithelioma, familial cylindromatosis, Brooke-Spiegler syndrome (ClinVar).

How common is CYLD p.Leu773= (c.2319G>A) in the general population?

CYLD p.Leu773= (c.2319G>A) is rare (popmax 0.396%, eas) (gnomAD).

How is Brooke-Spiegler syndrome inherited?

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

CYLD p.Leu773=

c.2319G>A · rs199912760 · VCV319507

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

rare (popmax 0.396%, eas)

Conditions

familial multiple trichoepithelioma

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 4.5	GERP 1.4, phastCons 1
Overall
CADD	13.04	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.396% East Asian · 176/44,434 alleles

Filtering AF 0.348% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.33%

Overall 0.012% 187/1,555,926 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.396%	252
Remaining individualsnot grpmax-eligible	0.00664%	15,060
European (non-Finnish)	0.000619%	161,634

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.Leu773=
Coding: c.2319G>A
dbSNP: rs199912760
Type: single nucleotide variant
Location: chr16:50792674 (GRCh38)

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

For Brooke-Spiegler syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult

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-leu773 (accessed [today's date]).

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