Is EXOSC2 p.Arg87Ter (c.259C>T) pathogenic?

EXOSC2 p.Arg87Ter (c.259C>T) is classified Uncertain significance in EXOSC2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-11-20). Very rare (popmax 0.00297%, nfe).

How common is EXOSC2 p.Arg87Ter (c.259C>T) in the general population?

EXOSC2 p.Arg87Ter (c.259C>T) is very rare (popmax 0.00297%, nfe) (gnomAD).

EXOSC2 p.Arg87Ter

c.259C>T · rs748372672 · VCV1018627

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00297%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 3 of 9
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.8	GERP -0.98, phastCons 1
Overall
CADD	36.0	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 0.00297% European (non-Finnish) · 35/1,179,958 alleles

Filtering AF 0.00215% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00191%

Overall 0.00248% 40/1,613,878 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00297%	33,713
African / African-American	0.00267%	37,446
South Asian	0.0022%	45,542
Remaining individualsnot grpmax-eligible	0.0016%	62,478

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.Arg87Ter
Coding: c.259C>T
MANE Select: NM_014285
dbSNP: rs748372672
Type: single nucleotide variant
Location: chr9:130697616 (GRCh38)
Gene constraint: LOEUF 1.009 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.25 · 8 PDB
Residue 87: the s1 motif domain; a β-strand

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

Similar variants

EXOSC2 p.Arg87Leu Uncertain significance ★★ ⚠ same residue
EXOSC2 p.Arg87Gln Conflicting classifications of pathogenicity ★ same residue
EXOSC2 p.Arg181Trp Uncertain significance ★★ ⚠ same type
EXOSC2 p.Arg236Trp Uncertain significance ★★ ⚠ same type
EXOSC2 p.Arg238Gln Uncertain significance ★★ ⚠ same type
EXOSC2 p.Arg238Trp Uncertain significance ★★ ⚠ same type
EXOSC2 p.Arg285Cys Uncertain significance ★★ ⚠ same type
EXOSC2 p.Arg62Thr Uncertain significance ★★ 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-arg87ter (accessed [today's date]).

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