Is EXOSC2 p.Arg287fs (c.859_862del) pathogenic?

EXOSC2 p.Arg287fs (c.859862del) is classified Uncertain significance in EXOSC2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-04-23). Very rare (popmax 0.00237%, nfe).

How common is EXOSC2 p.Arg287fs (c.859_862del) in the general population?

EXOSC2 p.Arg287fs (c.859_862del) is very rare (popmax 0.00237%, nfe) (gnomAD).

EXOSC2 p.Arg287fs

c.859_862del · rs765822902 · VCV2097002

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00237%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (9 of 9) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.5	GERP 1.4, 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 0.00237% European (non-Finnish) · 28/1,179,878 alleles

Filtering AF 0.00165% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00142%

Overall 0.00198% 32/1,613,778 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0048%	20,827
European (non-Finnish)grpmax	0.00237%	42,138
African / African-American	0.00133%	74,920

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: EXOSC2
Protein: p.Arg287fs
Coding: c.859_862del
MANE Select: NM_014285
dbSNP: rs765822902
Type: Deletion
Location: chr9:130703751 (GRCh38)
Gene constraint: LOEUF 1.009 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.25 · 8 PDB
Residue 287: an α-helix

Full EXOSC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EXOSC2 p.Arg236fs Uncertain significance ★ same type
EXOSC2 p.Gln168fs Uncertain significance ★ same type
EXOSC2 p.Gly218fs Uncertain significance ★ same type
EXOSC2 p.Met277fs Uncertain significance ★ same type
EXOSC2 p.Pro8fs Uncertain significance ★ same type
EXOSC2 p.Tyr260del Uncertain significance ★ same type
EXOSC2 c.224+12del Benign ★ same type
EXOSC2 c.360+20_360+47del Likely benign ★ 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/exosc2-p-arg287fs (accessed [today's date]).

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