Is CYLD p.Asp804= (c.2412C>T) pathogenic?

CYLD p.Asp804= (c.2412C>T) is classified Benign in CYLD (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-04). Common (popmax 23.2%, sas) — too common for a highly-penetrant pathogenic allele; Associated with familial multiple trichoepithelioma.

What condition is associated with CYLD p.Asp804= (c.2412C>T)?

CYLD p.Asp804= (c.2412C>T) is associated with familial multiple trichoepithelioma, familial cylindromatosis, Brooke-Spiegler syndrome (ClinVar).

How is Brooke-Spiegler syndrome inherited?

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

CYLD p.Asp804=

Q: How common is CYLD p.Asp804= (c.2412C>T) in the general population?

CYLD p.Asp804= (c.2412C>T) is common (popmax 23.2%, sas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.2412C>T · rs2066852 · VCV319508

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Common

common (popmax 23.2%, sas) — too common for a highly-penetrant pathogenic allele

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 -13	GERP -3.6
Overall
CADD	0.229	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 23.2% South Asian · 21,111/91,050 alleles

Filtering AF 22.9% ClinGen BA1/BS1 input FAF95, joint · FAF99 22.8%

Overall 8.07% 130,203/1,613,574 alleles · common

Ancestry group	Frequency	1 in
South Asiangrpmax	23.2%	4
Middle Eastern	16.8%	6
Ashkenazi Jewishnot grpmax-eligible	13.4%	7
Remaining individualsnot grpmax-eligible	8.75%	11
European (non-Finnish)	7.42%	13
East Asian	6.19%	16
Amishnot grpmax-eligible	5.92%	17
Admixed American	4.98%	20
Finnishnot grpmax-eligible	4.75%	21
African / African-American	2.98%	34

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.Asp804=
Coding: c.2412C>T
MANE Select: NM_001378743
dbSNP: rs2066852
Type: single nucleotide variant
Location: chr16:50793607 (GRCh38)
Gene constraint: LOEUF 0.325 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.06 · 6 PDB
Residue 804: the 'b-box' region; 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

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.Asp804Asn Uncertain significance ★ ⚠ same residue
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

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-asp804 (accessed [today's date]).

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