Is EXOSC2 p.Gln92His (c.276A>C) pathogenic?

EXOSC2 p.Gln92His (c.276A>C) is classified Uncertain significance in EXOSC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-10). AlphaMissense: likely pathogenic (0.7668); Very rare (popmax 8.47e-05%, nfe).

How common is EXOSC2 p.Gln92His (c.276A>C) in the general population?

EXOSC2 p.Gln92His (c.276A>C) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about EXOSC2 p.Gln92His (c.276A>C)?

AlphaMissense predicts likely pathogenic (score 0.7668) — an in-silico prediction, not a clinical call.

EXOSC2 p.Gln92His

c.276A>C · VCV4252021

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7668 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7668	likely pathogenic
REVEL	0.25	benign-leaning
SaProt	LLR -10.16	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.1	GERP -4.7
Regional constraint	o/e 0.95	unconstrained · MANE · 9,979 bp · p 0.3 · regional, not allelic
Overall
CADD	17.28	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,179,984 alleles

Overall 6.84e-05% 1/1,461,850 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: EXOSC2
Protein: p.Gln92His
Coding: c.276A>C
MANE Select: NM_014285
Type: single nucleotide variant
Location: chr9:130698167 (GRCh38)
Gene constraint: LOEUF 1.009 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.25 · 8 PDB
Residue 92: the s1 motif domain

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

Similar variants

EXOSC2 p.Gln92= Likely benign ★ 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
EXOSC2 p.Arg87Leu 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-gln92his (accessed [today's date]).

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