Is CYLD c.922+9C>A pathogenic?

CYLD c.922+9C>A is classified Benign in CYLD (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-13). Rare (popmax 0.167%, sas); Associated with Brooke-Spiegler syndrome.

What condition is associated with CYLD c.922+9C>A?

CYLD c.922+9C>A is associated with Brooke-Spiegler syndrome, familial cylindromatosis, familial multiple trichoepithelioma (ClinVar).

How common is CYLD c.922+9C>A in the general population?

CYLD c.922+9C>A is rare (popmax 0.167%, sas) (gnomAD).

How is Brooke-Spiegler syndrome inherited?

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

CYLD c.922+9C>A

rs528253971 · VCV319500

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

rare (popmax 0.167%, sas)

Conditions

Brooke-Spiegler syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
Splice region	donor +9	near-intronic (+9 nt from the splice site)
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.048	GERP -0.11
Non-coding constraint	Z 0.06	1 kb window · o/e 1.00 · regional · uncalibrated
Overall
CADD	12.85	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.167% South Asian · 152/90,824 alleles

Filtering AF 0.146% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.137%

Overall 0.0101% 161/1,595,970 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.167%	598
Remaining individualsnot grpmax-eligible	0.0129%	7,778
European (non-Finnish)	8.49e-05%	1,177,320

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
Coding: c.922+9C>A
MANE Select: NM_001378743
dbSNP: rs528253971
Type: single nucleotide variant
Location: chr16:50775183 (GRCh38)
Gene constraint: LOEUF 0.325 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.06 · 6 PDB

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

Disease context

Brooke-Spiegler syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: familial cylindromatosis familial multiple trichoepithelioma

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-c-922-plus-9c-a (accessed [today's date]).

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