Is EXOSC9 p.Arg111fs (c.329dup) pathogenic?

EXOSC9 p.Arg111fs (c.329dup) is classified Conflicting classifications of pathogenicity in EXOSC9 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2023-12-18). Very rare (popmax 0.00667%, afr).

How common is EXOSC9 p.Arg111fs (c.329dup) in the general population?

EXOSC9 p.Arg111fs (c.329dup) is very rare (popmax 0.00667%, afr) (gnomAD).

EXOSC9 p.Arg111fs

c.329dup · rs754121759 · VCV1691025

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00667%, afr)

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 4 of 12
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 2.7	GERP 1.9, phastCons 1
Overall
CADD	34.0	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 0.00667% African / African-American · 5/74,912 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00161%

Overall 0.000496% 8/1,613,962 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00667%	14,982
Admixed American	0.00167%	60,000
European (non-Finnish)	0.000169%	589,991

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: EXOSC9
Protein: p.Arg111fs
Coding: c.329dup
MANE Select: NM_005033
dbSNP: rs754121759
Type: Duplication
Location: chr4:121802961 (GRCh38)
Gene constraint: LOEUF 1.121 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.44 · 8 PDB
Residue 111: the 'are binding' region

Full EXOSC9 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EXOSC9 p.Arg111Ser Uncertain significance ★★ ⚠ same residue
EXOSC9 p.Pro302_Ile303insSerIleTer Pathogenic ★ same type
EXOSC9 p.Ile411fs Uncertain significance ★ same type
EXOSC9 c.1156+24_1156+26dup Benign ★ same type
EXOSC9 c.1157-21dup Benign ★ same type
EXOSC9 c.1157-6dup Benign ★ same type
EXOSC9 p.Arg162fs Pathogenic same type

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/exosc9-p-arg111fs (accessed [today's date]).

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