Is EXOSC3 p.Arg73= (c.219C>A) pathogenic?

EXOSC3 p.Arg73= (c.219C>A) is classified Likely benign in EXOSC3 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-02). Rare (popmax 0.205%, afr); Associated with pontocerebellar hypoplasia type 1B.

What condition is associated with EXOSC3 p.Arg73= (c.219C>A)?

EXOSC3 p.Arg73= (c.219C>A) is associated with pontocerebellar hypoplasia type 1B (ClinVar).

How common is EXOSC3 p.Arg73= (c.219C>A) in the general population?

EXOSC3 p.Arg73= (c.219C>A) is rare (popmax 0.205%, afr) (gnomAD).

EXOSC3 p.Arg73=

c.219C>A · rs149583035 · VCV510036

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

rare (popmax 0.205%, afr)

Conditions

pontocerebellar hypoplasia type 1B

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.99	GERP -0.46, phastCons 0.99
Overall
CADD	9.839	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.205% African / African-American · 154/74,952 alleles

Filtering AF 0.179% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.169%

Overall 0.0104% 167/1,608,404 alleles · rare exomes 82/1,456,064 · genomes 85/152,340 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.205%	487
Remaining individualsnot grpmax-eligible	0.0113%	8,886
Admixed American	0.0101%	9,891

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.Arg73=
Coding: c.219C>A
MANE Select: NM_016042
dbSNP: rs149583035
Type: single nucleotide variant
Location: chr9:37784826 (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 73: a β-strand

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.Arg73Pro 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-arg73 (accessed [today's date]).

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