Is CYLD p.Gln403Pro (c.1208A>C) pathogenic?

CYLD p.Gln403Pro (c.1208A>C) is classified Uncertain significance in CYLD (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-01). AlphaMissense: likely benign (0.0724); Absent from gnomAD v4.1; Associated with frontotemporal dementia and/or amyotrophic lateral sclerosis 8.

What condition is associated with CYLD p.Gln403Pro (c.1208A>C)?

CYLD p.Gln403Pro (c.1208A>C) is associated with frontotemporal dementia and/or amyotrophic lateral sclerosis 8 (ClinVar).

How common is CYLD p.Gln403Pro (c.1208A>C) in the general population?

CYLD p.Gln403Pro (c.1208A>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CYLD p.Gln403Pro (c.1208A>C)?

AlphaMissense predicts likely benign (score 0.0724) — an in-silico prediction, not a clinical call.

CYLD p.Gln403Pro

Q: How is Frontotemporal dementia with motor neuron disease inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.1208A>C · rs1970030063 · VCV3241235

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0724 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

frontotemporal dementia and/or amyotrophic lateral sclerosis 8

Computational evidence

Protein change
AlphaMissense	0.0724	likely benign
REVEL	0.398	indeterminate
SaProt	LLR -3.80	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	Δ0.41	acceptor loss, 2 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 11	GERP 2.2, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 3,800 bp · p 0.045 · regional, not allelic
Overall
CADD	22.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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.Gln403Pro
Coding: c.1208A>C
MANE Select: NM_001378743
dbSNP: rs1970030063
Type: single nucleotide variant
Location: chr16:50779734 (GRCh38)
Gene constraint: LOEUF 0.325 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.06 · 6 PDB
Residue 403: 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

frontotemporal dementia and/or amyotrophic lateral sclerosis 8 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Frontotemporal dementia with motor neuron disease (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

CYLD p.Gln403= Likely benign ★ same residue
CYLD p.Arg936Ter Pathogenic/Likely pathogenic ★★ same condition
CYLD p.Lys767Ter Pathogenic ★★ same condition
CYLD p.Ser371Ter Pathogenic ★★ same condition
CYLD p.Ala217Thr Uncertain significance ★★ ⚠ same condition
CYLD p.Arg147Cys Uncertain significance ★★ ⚠ same condition
CYLD p.Arg53His Uncertain significance ★★ ⚠ same condition
CYLD p.Ile232Val 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-gln403pro (accessed [today's date]).

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