Is CYLD p.Cys513Ser (c.1538G>C) pathogenic?

CYLD p.Cys513Ser (c.1538G>C) is classified Uncertain significance in CYLD (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-05). AlphaMissense: likely pathogenic (0.8907); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with CYLD p.Cys513Ser (c.1538G>C)?

CYLD p.Cys513Ser (c.1538G>C) is associated with Inborn genetic diseases (ClinVar).

How common is CYLD p.Cys513Ser (c.1538G>C) in the general population?

CYLD p.Cys513Ser (c.1538G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CYLD p.Cys513Ser (c.1538G>C)?

AlphaMissense predicts likely pathogenic (score 0.8907) — an in-silico prediction, not a clinical call.

CYLD p.Cys513Ser

c.1538G>C · VCV3499014

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8907 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8907	likely pathogenic
REVEL	0.556	indeterminate
SaProt	LLR -5.04	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.4, phastCons 1
Regional constraint	o/e 0.38	unconstrained · MANE · 13 kb · p 1.1e-28 · regional, not allelic
Overall
CADD	23.6	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.Cys513Ser
Coding: c.1538G>C
MANE Select: NM_001378743
Type: single nucleotide variant
Location: chr16:50781265 (GRCh38)
Gene constraint: LOEUF 0.325 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.06 · 6 PDB
Residue 513: the cap-gly 3 domain; the 'interaction with trip' region; the 'interaction with ikbkg/nemo' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CYLD p.Cys513fs Pathogenic ★★ same residue
CYLD p.Thr311Met Uncertain significance ★★ ⚠ same condition
CYLD p.Arg929Thr Uncertain significance ★ ⚠ same condition
CYLD p.Asn271Lys Uncertain significance ★ ⚠ same condition
CYLD p.Asn574Ser Uncertain significance ★ same condition
CYLD p.Asn68Lys Uncertain significance ★ ⚠ same condition
CYLD p.Asp383Tyr Uncertain significance ★ same condition
CYLD p.Asp394Gly 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-cys513ser (accessed [today's date]).

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