Is CYLD p.Asp85Val (c.254A>T) pathogenic?

CYLD p.Asp85Val (c.254A>T) is classified Uncertain significance in CYLD (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-23). AlphaMissense: ambiguous (0.5481); Very rare (popmax 0.00133%, afr).

How common is CYLD p.Asp85Val (c.254A>T) in the general population?

CYLD p.Asp85Val (c.254A>T) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about CYLD p.Asp85Val (c.254A>T)?

AlphaMissense predicts ambiguous (score 0.5481) — an in-silico prediction, not a clinical call.

CYLD p.Asp85Val

c.254A>T · VCV3360386

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5481 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5481	ambiguous
REVEL	0.829	moderately pathogenic-leaning
SaProt	LLR -10.14	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.4, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 435 bp · p 0.072 · regional, not allelic
Overall
CADD	25.5	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 0.00133% African / African-American · 1/75,058 alleles

Overall 6.84e-05% 1/1,461,810 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.Asp85Val
Coding: c.254A>T
MANE Select: NM_001378743
Type: single nucleotide variant
Location: chr16:50749952 (GRCh38)
Gene constraint: LOEUF 0.325 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.06 · 6 PDB

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-asp85val (accessed [today's date]).

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