Is CYLD p.Arg397Ser (c.1189C>A) pathogenic?

CYLD p.Arg397Ser (c.1189C>A) is classified Benign in CYLD (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-01). AlphaMissense: likely benign (0.1377); Ultra-rare (popmax 0.0201%, eas); Associated with ovarian cancer.

What condition is associated with CYLD p.Arg397Ser (c.1189C>A)?

CYLD p.Arg397Ser (c.1189C>A) is associated with ovarian cancer (ClinVar).

How common is CYLD p.Arg397Ser (c.1189C>A) in the general population?

CYLD p.Arg397Ser (c.1189C>A) is ultra-rare (popmax 0.0201%, eas) (gnomAD).

What do computational predictors say about CYLD p.Arg397Ser (c.1189C>A)?

AlphaMissense predicts likely benign (score 0.1377) — an in-silico prediction, not a clinical call.

CYLD p.Arg397Ser

c.1189C>A · rs149427272 · VCV2445310

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1377 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0201%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ovarian cancer

Computational evidence

Protein change
AlphaMissense	0.1377	likely benign
REVEL	0.256	benign-leaning
SaProt	LLR -4.51	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.20 · evaluated, not missing
Constraint at this position
Conservation	phyloP 5.9	GERP 1.4, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 3,800 bp · p 0.045 · regional, not allelic
Overall
CADD	18.11	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 0.0201% East Asian · 9/44,878 alleles

Filtering AF 0.0104% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00779%

Overall 0.000682% 11/1,613,816 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0201%	4,986
South Asian	0.0022%	45,518

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.Arg397Ser
Coding: c.1189C>A
MANE Select: NM_001378743
dbSNP: rs149427272
Type: single nucleotide variant
Location: chr16:50779715 (GRCh38)
Gene constraint: LOEUF 0.325 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.06 · 6 PDB
Residue 397: the 'interaction with trip' region; the 'disordered' region; the 'interaction with traf2' region

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

Disease context

ovarian cancer — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CYLD p.Arg397His Conflicting classifications of pathogenicity ★ ⚠ same residue
CYLD p.Asn335Ser Benign ★ same condition
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

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-arg397ser (accessed [today's date]).

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