Is CYLD p.Pro42Leu (c.125C>T) pathogenic?

CYLD p.Pro42Leu (c.125C>T) is classified Uncertain significance in CYLD (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-19). AlphaMissense: likely benign (0.2645); Ultra-rare (popmax 0.0164%, mid); Associated with frontotemporal dementia and/or amyotrophic lateral sclerosis 8.

What condition is associated with CYLD p.Pro42Leu (c.125C>T)?

CYLD p.Pro42Leu (c.125C>T) is associated with frontotemporal dementia and/or amyotrophic lateral sclerosis 8 (ClinVar).

How common is CYLD p.Pro42Leu (c.125C>T) in the general population?

CYLD p.Pro42Leu (c.125C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about CYLD p.Pro42Leu (c.125C>T)?

AlphaMissense predicts likely benign (score 0.2645) — an in-silico prediction, not a clinical call.

CYLD p.Pro42Leu

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.125C>T · rs770539079 · VCV2681043

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2645 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

frontotemporal dementia and/or amyotrophic lateral sclerosis 8

Computational evidence

Protein change
AlphaMissense	0.2645	likely benign
REVEL	0.409	indeterminate
SaProt	LLR -10.01	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.4, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 435 bp · p 0.072 · regional, not allelic
Overall
CADD	23.2	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 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.00347% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00229%

Overall 0.00211% 34/1,613,880 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
African / African-American	0.00802%	12,476
South Asian	0.00329%	30,357
Remaining individualsnot grpmax-eligible	0.0032%	31,241
European (non-Finnish)	0.00186%	53,637

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.Pro42Leu
Coding: c.125C>T
MANE Select: NM_001378743
dbSNP: rs770539079
Type: single nucleotide variant
Location: chr16:50749823 (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

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.Pro42= Benign/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-pro42leu (accessed [today's date]).

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