Is CYLD p.Leu82Phe (c.244C>T) pathogenic?

CYLD p.Leu82Phe (c.244C>T) is classified Uncertain significance in CYLD (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-21). AlphaMissense: ambiguous (0.4148); Very rare (popmax 0.00161%, nfe); Associated with familial cylindromatosis.

What condition is associated with CYLD p.Leu82Phe (c.244C>T)?

CYLD p.Leu82Phe (c.244C>T) is associated with familial cylindromatosis, Brooke-Spiegler syndrome, frontotemporal dementia and/or amyotrophic lateral sclerosis 8 (ClinVar).

How common is CYLD p.Leu82Phe (c.244C>T) in the general population?

CYLD p.Leu82Phe (c.244C>T) is very rare (popmax 0.00161%, nfe) (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.Leu82Phe (c.244C>T)?

AlphaMissense predicts ambiguous (score 0.4148) — an in-silico prediction, not a clinical call.

CYLD p.Leu82Phe

c.244C>T · VCV3580754

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4148 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00161%, nfe)

Conditions

familial cylindromatosis

Computational evidence

Protein change
AlphaMissense	0.4148	ambiguous
REVEL	0.606	indeterminate
SaProt	LLR -7.45	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.3	GERP 2.4, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 435 bp · p 0.072 · regional, not allelic
Overall
CADD	23.7	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 0.00161% European (non-Finnish) · 19/1,180,028 alleles

Filtering AF 0.00103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00083%

Overall 0.00118% 19/1,614,002 alleles · very rare

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.Leu82Phe
Coding: c.244C>T
MANE Select: NM_001378743
Type: single nucleotide variant
Location: chr16:50749942 (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 cylindromatosis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Brooke-Spiegler syndrome frontotemporal dementia and/or amyotrophic lateral sclerosis 8 trichoepithelioma, multiple familial, 1

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-leu82phe (accessed [today's date]).

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