Is AOPEP p.Cys378fs (c.1134_1135del) pathogenic?

AOPEP p.Cys378fs (c.11341135del) is classified Conflicting classifications of pathogenicity in AOPEP (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-12-01). Very rare (popmax 0.0011%, nfe); Associated with dystonia 31.

What condition is associated with AOPEP p.Cys378fs (c.1134_1135del)?

AOPEP p.Cys378fs (c.1134_1135del) is associated with dystonia 31 (ClinVar).

How common is AOPEP p.Cys378fs (c.1134_1135del) in the general population?

AOPEP p.Cys378fs (c.1134_1135del) is very rare (popmax 0.0011%, nfe) (gnomAD).

AOPEP p.Cys378fs

c.1134_1135del · VCV3779336

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.0011%, nfe)

Conditions

dystonia 31

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 5 of 17
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 12	GERP 2.4, phastCons 1
Overall
CADD	21.8	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% European (non-Finnish) · 13/1,179,932 alleles

Filtering AF 0.000615% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000474%

Overall 0.000805% 13/1,613,946 alleles · very rare

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.Cys378fs
Coding: c.1134_1135del
MANE Select: NM_001193329
Type: Deletion
Location: chr9:94800772 (GRCh38)
Gene constraint: LOEUF 0.979 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.36
Residue 378: 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

FANCC p.Ala378= Likely benign ★★ same residue
AOPEP p.Lys73fs Likely pathogenic ★ same condition
AOPEP p.Met582fs Pathogenic ★ same condition
AOPEP p.Val406fs Likely pathogenic ★ same condition
FANCC p.Ala378Thr Uncertain significance ★ ⚠ same residue
AOPEP p.Gln235Ter Likely pathogenic ★★ same condition
AOPEP p.Arg401Trp Uncertain significance ★★ ⚠ same condition
AOPEP c.964+2T>G 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-cys378fs (accessed [today's date]).

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