Is CYLD p.Arg53His (c.158G>A) pathogenic?

CYLD p.Arg53His (c.158G>A) is classified Uncertain significance in CYLD (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-03-03). AlphaMissense: likely benign (0.3215); Very rare (popmax 0.00933%, afr); Associated with frontotemporal dementia and/or amyotrophic lateral sclerosis 8.

What condition is associated with CYLD p.Arg53His (c.158G>A)?

CYLD p.Arg53His (c.158G>A) is associated with frontotemporal dementia and/or amyotrophic lateral sclerosis 8 (ClinVar).

How common is CYLD p.Arg53His (c.158G>A) in the general population?

CYLD p.Arg53His (c.158G>A) is very rare (popmax 0.00933%, afr) (gnomAD).

What do computational predictors say about CYLD p.Arg53His (c.158G>A)?

AlphaMissense predicts likely benign (score 0.3215) — an in-silico prediction, not a clinical call.

CYLD p.Arg53His

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.158G>A · rs375455772 · VCV2885534

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.3215 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00933%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

frontotemporal dementia and/or amyotrophic lateral sclerosis 8

Computational evidence

Protein change
AlphaMissense	0.3215	likely benign
REVEL	0.575	indeterminate
SaProt	LLR -6.42	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 12	GERP 2.4, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 435 bp · p 0.072 · regional, not allelic
Overall
CADD	25.8	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

Grpmax group 0.00933% African / African-American · 7/75,024 alleles

Filtering AF 0.00437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00308%

Overall 0.00192% 31/1,614,110 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0096%	10,418
African / African-Americangrpmax	0.00933%	10,718
Admixed American	0.00833%	12,002
South Asian	0.0022%	45,540
European (non-Finnish)	0.000932%	107,274

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg53His
Coding: c.158G>A
MANE Select: NM_001378743
dbSNP: rs375455772
Type: single nucleotide variant
Location: chr16:50749856 (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.Arg53Cys Uncertain significance ★ ⚠ 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.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-arg53his (accessed [today's date]).

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