Is CYLD p.Arg758Gln (c.2273G>A) pathogenic?

CYLD p.Arg758Gln (c.2273G>A) is classified Uncertain significance in CYLD (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-17). AlphaMissense: likely pathogenic (0.9986); Very rare (popmax 8.53e-05%, nfe).

How common is CYLD p.Arg758Gln (c.2273G>A) in the general population?

CYLD p.Arg758Gln (c.2273G>A) is very rare (popmax 8.53e-05%, nfe) (gnomAD).

What do computational predictors say about CYLD p.Arg758Gln (c.2273G>A)?

AlphaMissense predicts likely pathogenic (score 0.9986) — an in-silico prediction, not a clinical call.

CYLD p.Arg758Gln

c.2273G>A · VCV3364289

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9986 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.53e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9986	likely pathogenic · top 7% in CYLD
REVEL	0.868	moderately pathogenic-leaning
SaProt	LLR -13.82	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 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	27.9	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

Grpmax group 8.53e-05% European (non-Finnish) · 1/1,172,734 alleles

Overall 6.88e-05% 1/1,452,516 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.Arg758Gln
Coding: c.2273G>A
MANE Select: NM_001378743
Type: single nucleotide variant
Location: chr16:50792628 (GRCh38)
Gene constraint: LOEUF 0.325 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.06 · 6 PDB
Residue 758: the usp domain

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

Similar variants

CYLD p.Arg758Ter Pathogenic ★★ same residue
CYLD p.Arg235Ter Pathogenic/Likely 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-arg758gln (accessed [today's date]).

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