Is EXOSC3 p.Arg18Pro (c.53G>C) pathogenic?

EXOSC3 p.Arg18Pro (c.53G>C) is classified Conflicting classifications of pathogenicity in EXOSC3 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-08-01). AlphaMissense: likely benign (0.1387); Rare (popmax 0.251%, sas); Associated with Inborn genetic diseases.

What condition is associated with EXOSC3 p.Arg18Pro (c.53G>C)?

EXOSC3 p.Arg18Pro (c.53G>C) is associated with Inborn genetic diseases, pontocerebellar hypoplasia type 1B (ClinVar).

How common is EXOSC3 p.Arg18Pro (c.53G>C) in the general population?

EXOSC3 p.Arg18Pro (c.53G>C) is rare (popmax 0.251%, sas) (gnomAD).

What do computational predictors say about EXOSC3 p.Arg18Pro (c.53G>C)?

AlphaMissense predicts likely benign (score 0.1387) — an in-silico prediction, not a clinical call.

EXOSC3 p.Arg18Pro

c.53G>C · rs145677716 · VCV746975

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1387 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.251%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1387	likely benign
REVEL	0.403	indeterminate
SaProt	LLR -7.06	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.6, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 4,362 bp · p 0.097 · regional, not allelic
Overall
CADD	22.7	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 0.251% South Asian · 228/90,968 alleles

Filtering AF 0.224% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.214%

Overall 0.0494% 796/1,610,026 alleles · rare exomes 733/1,457,666 · genomes 63/152,360 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	1.05%	95
South Asiangrpmax	0.251%	399
Remaining individualsnot grpmax-eligible	0.119%	842
Middle Eastern	0.0991%	1,009
Admixed American	0.0684%	1,462
European (non-Finnish)	0.0111%	8,993
African / African-American	0.00533%	18,753
East Asian	0.00446%	22,401

Ashkenazi Jewish 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: EXOSC3
Protein: p.Arg18Pro
Coding: c.53G>C
MANE Select: NM_016042
dbSNP: rs145677716
Type: single nucleotide variant
Location: chr9:37784992 (GRCh38)
Gene constraint: LOEUF 1.072 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 80.26 · 8 PDB
Residue 18: a β-strand

Full EXOSC3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: pontocerebellar hypoplasia type 1B

Similar variants

EXOSC3 p.Arg18Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
EXOSC3 p.Arg18Ser Uncertain significance ★★ same residue
EXOSC3 p.Arg186Ter Pathogenic/Likely pathogenic ★★ same condition
EXOSC3 p.Asp132Ala Pathogenic ★★ same condition
EXOSC3 p.Gly191Asp Likely pathogenic ★★ same condition
EXOSC3 p.Gly31Ala Pathogenic/Likely pathogenic ★★ same condition
EXOSC3 p.Met1Thr Pathogenic/Likely pathogenic ★★ same condition
EXOSC3 p.Met1Val Pathogenic/Likely pathogenic ★★ same condition

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/exosc3-p-arg18pro (accessed [today's date]).

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