Is EXOSC2 p.Gln247Arg (c.740A>G) pathogenic?

EXOSC2 p.Gln247Arg (c.740A>G) is classified Uncertain significance in EXOSC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-10). AlphaMissense: likely benign (0.0825); Very rare (popmax 0.00445%, eas).

How common is EXOSC2 p.Gln247Arg (c.740A>G) in the general population?

EXOSC2 p.Gln247Arg (c.740A>G) is very rare (popmax 0.00445%, eas) (gnomAD).

What do computational predictors say about EXOSC2 p.Gln247Arg (c.740A>G)?

AlphaMissense predicts likely benign (score 0.0825) — an in-silico prediction, not a clinical call.

EXOSC2 p.Gln247Arg

c.740A>G · VCV3846836

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0825 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00445%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0825	likely benign
REVEL	0.216	benign-leaning
SaProt	LLR -6.21	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.3, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 9,979 bp · p 0.3 · regional, not allelic
Overall
CADD	22.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00445% East Asian · 2/44,896 alleles

Filtering AF 0.000738% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.000124% 2/1,613,816 alleles · very rare exomes 1/1,461,662 · genomes 1/152,154 · joint denominator

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.Gln247Arg
Coding: c.740A>G
MANE Select: NM_014285
Type: single nucleotide variant
Location: chr9:130703120 (GRCh38)
Gene constraint: LOEUF 1.009 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.25 · 8 PDB
Residue 247: an α-helix

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

Similar variants

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
EXOSC2 p.Arg87Ter 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-gln247arg (accessed [today's date]).

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