Is EXOSC3 p.Ala13Pro (c.37G>C) pathogenic?

EXOSC3 p.Ala13Pro (c.37G>C) is classified Conflicting classifications of pathogenicity in EXOSC3 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-01-26). AlphaMissense: likely benign (0.0651); Very rare (popmax 0.00836%, amr); Associated with pontocerebellar hypoplasia type 1B.

What condition is associated with EXOSC3 p.Ala13Pro (c.37G>C)?

EXOSC3 p.Ala13Pro (c.37G>C) is associated with pontocerebellar hypoplasia type 1B (ClinVar).

How common is EXOSC3 p.Ala13Pro (c.37G>C) in the general population?

EXOSC3 p.Ala13Pro (c.37G>C) is very rare (popmax 0.00836%, amr) (gnomAD).

What do computational predictors say about EXOSC3 p.Ala13Pro (c.37G>C)?

AlphaMissense predicts likely benign (score 0.0651) — an in-silico prediction, not a clinical call.

EXOSC3 p.Ala13Pro

c.37G>C · rs758230758 · VCV935731

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0651 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00836%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

pontocerebellar hypoplasia type 1B

Computational evidence

Protein change
AlphaMissense	0.0651	likely benign
REVEL	0.091	moderately benign-leaning
SaProt	LLR -5.46	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 -0.12	GERP -1.6
Regional constraint	o/e 1.09	unconstrained · MANE · 4,362 bp · p 0.097 · regional, not allelic
Overall
CADD	14.33	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 0.00836% Admixed American · 5/59,828 alleles

Filtering AF 0.00324% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00207%

Overall 0.00131% 21/1,604,302 alleles · very rare exomes 17/1,452,076 · genomes 4/152,226 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00836%	11,966
Remaining individualsnot grpmax-eligible	0.00161%	61,932
African / African-American	0.00134%	74,770
European (non-Finnish)	0.00119%	83,867

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.Ala13Pro
Coding: c.37G>C
MANE Select: NM_016042
dbSNP: rs758230758
Type: single nucleotide variant
Location: chr9:37785008 (GRCh38)
Gene constraint: LOEUF 1.072 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 80.26 · 8 PDB

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

Disease context

pontocerebellar hypoplasia type 1B — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

EXOSC3 p.Ala13Thr 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
EXOSC3 p.Val80Phe 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-ala13pro (accessed [today's date]).

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