Is CYLD p.Leu227Pro (c.680T>C) pathogenic?

CYLD p.Leu227Pro (c.680T>C) is classified Uncertain significance in CYLD (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-10). AlphaMissense: likely benign (0.1202); Absent from gnomAD v4.1; Associated with frontotemporal dementia and/or amyotrophic lateral sclerosis 8.

What condition is associated with CYLD p.Leu227Pro (c.680T>C)?

CYLD p.Leu227Pro (c.680T>C) is associated with frontotemporal dementia and/or amyotrophic lateral sclerosis 8 (ClinVar).

How common is CYLD p.Leu227Pro (c.680T>C) in the general population?

CYLD p.Leu227Pro (c.680T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CYLD p.Leu227Pro (c.680T>C)?

AlphaMissense predicts likely benign (score 0.1202) — an in-silico prediction, not a clinical call.

CYLD p.Leu227Pro

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.680T>C · rs2150903968 · VCV2681078

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1202 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

frontotemporal dementia and/or amyotrophic lateral sclerosis 8

Computational evidence

Protein change
AlphaMissense	0.1202	likely benign
REVEL	0.293	indeterminate
SaProt	LLR -6.48	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.4	GERP 2.2, phastCons 0.97
Regional constraint	o/e 0.58	unconstrained · MANE · 26 kb · p 6.2e-10 · regional, not allelic
Overall
CADD	18.73	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.Leu227Pro
Coding: c.680T>C
MANE Select: NM_001378743
dbSNP: rs2150903968
Type: single nucleotide variant
Location: chr16:50751779 (GRCh38)
Gene constraint: LOEUF 0.325 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.06 · 6 PDB
Residue 227: the 'interaction with trip' 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.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
CYLD p.Ile588Thr 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-leu227pro (accessed [today's date]).

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