Is AOPEP p.Val406fs (c.1215del) pathogenic?

AOPEP p.Val406fs (c.1215del) is classified Likely pathogenic in AOPEP (ClinVar, Single submitter, 2 submitters; last evaluated 2023-07-18). Very rare (popmax 0.0078%, nfe); Associated with AOPEP-related disorder.

What condition is associated with AOPEP p.Val406fs (c.1215del)?

AOPEP p.Val406fs (c.1215del) is associated with AOPEP-related disorder, dystonia 31 (ClinVar).

How common is AOPEP p.Val406fs (c.1215del) in the general population?

AOPEP p.Val406fs (c.1215del) is very rare (popmax 0.0078%, nfe) (gnomAD).

AOPEP p.Val406fs

c.1215del · rs747916174 · VCV1319962

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.0078%, nfe)

Conditions

AOPEP-related disorder

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 7.5	GERP 2.4, phastCons 1
Overall
CADD	0.795	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 0.0078% European (non-Finnish) · 92/1,180,046 alleles

Filtering AF 0.00647% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.006%

Overall 0.00601% 97/1,614,216 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0078%	12,827
Remaining individualsnot grpmax-eligible	0.0048%	20,837
Admixed American	0.00167%	60,028
African / African-American	0.00133%	75,042

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.Val406fs
Coding: c.1215del
MANE Select: NM_001193329
dbSNP: rs747916174
Type: Deletion
Location: chr9:94800853 (GRCh38)
Gene constraint: LOEUF 0.979 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.36
Residue 406: a UniProt-annotated variant site (in dyt31)

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

Disease context

AOPEP-related disorder

Also linked: dystonia 31

Similar variants

FANCC p.Met406Thr Uncertain significance ★★ ⚠ same residue
AOPEP p.Lys73fs Likely pathogenic ★ same condition
AOPEP p.Met582fs Pathogenic ★ same condition
FANCC p.His363fs Likely pathogenic ★ same condition
AOPEP p.Cys378fs Conflicting classifications of pathogenicity ★ same condition
FANCC c.1329+181_1329+183del Conflicting classifications of pathogenicity same condition
AOPEP p.Gln235Ter Likely pathogenic ★★ same condition
FANCC c.844-1G>C Pathogenic/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-val406fs (accessed [today's date]).

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