Is CYLD p.Ala562Pro (c.1684G>C) pathogenic?

CYLD p.Ala562Pro (c.1684G>C) is classified Uncertain significance in CYLD (ClinVar, Single submitter, 1 submitter; last evaluated 2016-09-23). AlphaMissense: likely pathogenic (0.9817); Absent from gnomAD v4.1; Associated with familial cylindromatosis.

What condition is associated with CYLD p.Ala562Pro (c.1684G>C)?

CYLD p.Ala562Pro (c.1684G>C) is associated with familial cylindromatosis (ClinVar).

How common is CYLD p.Ala562Pro (c.1684G>C) in the general population?

CYLD p.Ala562Pro (c.1684G>C) is absent from gnomAD v4.1 (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.Ala562Pro (c.1684G>C)?

AlphaMissense predicts likely pathogenic (score 0.9817) — an in-silico prediction, not a clinical call.

CYLD p.Ala562Pro

c.1684G>C · rs886040877 · VCV267238

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9817 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

familial cylindromatosis

Computational evidence

Protein change
AlphaMissense	0.9817	likely pathogenic
REVEL	0.485	indeterminate
SaProt	LLR -4.80	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	Δ0.96	donor loss · deltas
Pangolin	Δ0.85	loss · gain 0.05 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 12	GERP 2.3, phastCons 1
Regional constraint	o/e 0.38	unconstrained · MANE · 13 kb · p 1.1e-28 · regional, not allelic
Overall
CADD	36.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CYLD
Protein: p.Ala562Pro
Coding: c.1684G>C
MANE Select: NM_001378743
dbSNP: rs886040877
Type: single nucleotide variant
Location: chr16:50781411 (GRCh38)
Gene constraint: LOEUF 0.325 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.06 · 6 PDB
Residue 562: the 'interaction with trip' region; an α-helix

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

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-p-ala562pro (accessed [today's date]).

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