Is CYLD p.Pro42= (c.126G>A) pathogenic?

CYLD p.Pro42= (c.126G>A) is classified Benign/Likely benign in CYLD (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-09-06). Ultra-rare (popmax 0.0433%, amr); Associated with familial multiple trichoepithelioma.

What condition is associated with CYLD p.Pro42= (c.126G>A)?

CYLD p.Pro42= (c.126G>A) is associated with familial multiple trichoepithelioma, familial cylindromatosis, Brooke-Spiegler syndrome (ClinVar).

How common is CYLD p.Pro42= (c.126G>A) in the general population?

CYLD p.Pro42= (c.126G>A) is ultra-rare (popmax 0.0433%, amr) (gnomAD).

How is Brooke-Spiegler syndrome inherited?

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

CYLD p.Pro42=

c.126G>A · rs202119806 · VCV319498

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0433%, amr)

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 -0.68	GERP -4.8
Overall
CADD	5.235	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0433% Admixed American · 26/60,008 alleles

Filtering AF 0.0397% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0384%

Overall 0.0359% 580/1,614,090 alleles · ultra-rare

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	1.97%	51
Admixed Americangrpmax	0.0433%	2,308
European (non-Finnish)	0.0428%	2,337
Remaining individualsnot grpmax-eligible	0.024%	4,167
Middle Eastern	0.0165%	6,062
African / African-American	0.0133%	7,501
Ashkenazi Jewishnot grpmax-eligible	0.00676%	14,800
East Asian	0.00223%	44,880
Finnishnot grpmax-eligible	0.00156%	64,016
South Asian	0.0011%	91,072

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro42=
Coding: c.126G>A
MANE Select: NM_001378743
dbSNP: rs202119806
Type: single nucleotide variant
Location: chr16:50749824 (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

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

Similar variants

CYLD p.Pro42Leu 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-pro42 (accessed [today's date]).

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