Is AOPEP p.Arg401Trp (c.1201C>T) pathogenic?

AOPEP p.Arg401Trp (c.1201C>T) is classified Uncertain significance in AOPEP (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-24). AlphaMissense: ambiguous (0.5323); Ultra-rare (popmax 0.033%, mid); Associated with dystonia 31.

What condition is associated with AOPEP p.Arg401Trp (c.1201C>T)?

AOPEP p.Arg401Trp (c.1201C>T) is associated with dystonia 31 (ClinVar).

How common is AOPEP p.Arg401Trp (c.1201C>T) in the general population?

AOPEP p.Arg401Trp (c.1201C>T) is ultra-rare (popmax 0.033%, mid) (gnomAD).

What do computational predictors say about AOPEP p.Arg401Trp (c.1201C>T)?

AlphaMissense predicts ambiguous (score 0.5323) — an in-silico prediction, not a clinical call.

AOPEP p.Arg401Trp

c.1201C>T · VCV4057234

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5323 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.033%, mid)

Conditions

dystonia 31

Computational evidence

Protein change
AlphaMissense	0.5323	ambiguous
REVEL	0.369	indeterminate
SaProt	LLR -13.90	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.9	GERP 1.5, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 282 kb · p 0.54 · regional, not allelic
Overall
CADD	26.6	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 0.033% Middle Eastern · 2/6,062 alleles

Filtering AF 0.00582% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00431%

Overall 0.0052% 84/1,614,208 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.033%	3,031
Remaining individualsnot grpmax-eligible	0.0064%	15,628
European (non-Finnish)	0.00585%	17,102
East Asian	0.00446%	22,445
South Asian	0.00439%	22,769
Admixed American	0.00167%	60,028
Finnishnot grpmax-eligible	0.00156%	64,044
African / African-American	0.00133%	75,052

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: AOPEP
Protein: p.Arg401Trp
Coding: c.1201C>T
MANE Select: NM_001193329
Type: single nucleotide variant
Location: chr9:94800839 (GRCh38)
Gene constraint: LOEUF 0.979 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.36
Residue 401: a UniProt-annotated variant site (in dyt31)

Full AOPEP gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

dystonia 31 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

AOPEP p.Gln235Ter Likely pathogenic ★★ same condition
FANCC p.Gly401fs Pathogenic/Likely pathogenic ★★ same residue
AOPEP c.964+2T>G Pathogenic ★ same condition
AOPEP p.Arg255Ter Likely pathogenic ★ same condition
AOPEP p.Arg493Ter Pathogenic ★ same condition
AOPEP p.Trp259Ter Pathogenic same condition
AOPEP p.Arg230fs Likely pathogenic ★ same condition
AOPEP p.Lys73fs Likely pathogenic ★ 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/aopep-p-arg401trp (accessed [today's date]).

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