Is CYLD p.Ile20Ser (c.59T>G) pathogenic?

CYLD p.Ile20Ser (c.59T>G) is classified Conflicting classifications of pathogenicity in CYLD (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2023-12-02). AlphaMissense: ambiguous (0.3694); Very rare (popmax 0.00879%, sas); Associated with familial multiple trichoepithelioma.

What condition is associated with CYLD p.Ile20Ser (c.59T>G)?

CYLD p.Ile20Ser (c.59T>G) is associated with familial multiple trichoepithelioma, familial cylindromatosis, Brooke-Spiegler syndrome (ClinVar).

How common is CYLD p.Ile20Ser (c.59T>G) in the general population?

CYLD p.Ile20Ser (c.59T>G) is very rare (popmax 0.00879%, sas) (gnomAD).

How is Brooke-Spiegler syndrome inherited?

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

What do computational predictors say about CYLD p.Ile20Ser (c.59T>G)?

AlphaMissense predicts ambiguous (score 0.3694) — an in-silico prediction, not a clinical call.

CYLD p.Ile20Ser

c.59T>G · rs764097337 · VCV319497

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.3694 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00879%, sas)

Conditions

familial multiple trichoepithelioma

Computational evidence

Protein change
AlphaMissense	0.3694	ambiguous
REVEL	0.476	indeterminate
SaProt	LLR -5.82	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.14	GERP -3.5, phastCons 0.37
Regional constraint	o/e 0.86	unconstrained · MANE · 435 bp · p 0.072 · regional, not allelic
Overall
CADD	8.069	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00879% South Asian · 8/91,040 alleles

Filtering AF 0.00437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00312%

Overall 0.00297% 48/1,613,706 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00879%	11,380
Admixed American	0.00501%	19,975
European (non-Finnish)	0.00297%	33,714
Remaining individualsnot grpmax-eligible	0.0016%	62,472
African / African-American	0.00134%	74,888

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.Ile20Ser
Coding: c.59T>G
MANE Select: NM_001378743
dbSNP: rs764097337
Type: single nucleotide variant
Location: chr16:50749757 (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 frontotemporal dementia and/or amyotrophic lateral sclerosis 8

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.Ala217Thr Uncertain significance ★★ ⚠ same condition
CYLD p.Arg147Cys Uncertain significance ★★ ⚠ same condition
CYLD p.Arg53His 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-ile20ser (accessed [today's date]).

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