Is CYLD p.Cys866Arg (c.2596T>C) pathogenic?

CYLD p.Cys866Arg (c.2596T>C) is classified Uncertain significance in CYLD (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-20). AlphaMissense: likely pathogenic (0.9997); Absent from gnomAD v4.1.

How common is CYLD p.Cys866Arg (c.2596T>C) in the general population?

CYLD p.Cys866Arg (c.2596T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CYLD p.Cys866Arg (c.2596T>C)?

AlphaMissense predicts likely pathogenic (score 0.9997) — an in-silico prediction, not a clinical call.

CYLD p.Cys866Arg

c.2596T>C · VCV4742309

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9997 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9997	likely pathogenic · top 4% in CYLD
REVEL	0.808	moderately pathogenic-leaning
SaProt	LLR -15.19	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 2.2, phastCons 1
Regional constraint	o/e 0.59	unconstrained · MANE · 3,803 bp · p 1.2e-09 · regional, not allelic
Overall
CADD	31.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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.Cys866Arg
Coding: c.2596T>C
MANE Select: NM_001378743
Type: single nucleotide variant
Location: chr16:50794338 (GRCh38)
Gene constraint: LOEUF 0.325 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.06 · 6 PDB
Residue 866: a β-strand; the usp domain

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

Similar variants

CYLD p.Arg235Ter Pathogenic/Likely pathogenic ★★ same type
CYLD p.Arg758Ter Pathogenic ★★ same type
CYLD p.Arg936Ter Pathogenic/Likely pathogenic ★★ same type
CYLD p.Lys767Ter Pathogenic ★★ same type
CYLD p.Ser371Ter Pathogenic ★★ same type
CYLD p.Ser839Ter Pathogenic/Likely pathogenic ★★ same type
CYLD p.Trp847Ter Pathogenic ★★ same type
CYLD c.*3229C>T Uncertain significance ★★ same type

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-cys866arg (accessed [today's date]).

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