Is EXOSC3 p.Ala59Val (c.176C>T) pathogenic?

EXOSC3 p.Ala59Val (c.176C>T) is classified Uncertain significance in EXOSC3 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-05-16). AlphaMissense: likely benign (0.0809); Very rare (popmax 0.00068%, nfe); Associated with Inborn genetic diseases.

What condition is associated with EXOSC3 p.Ala59Val (c.176C>T)?

EXOSC3 p.Ala59Val (c.176C>T) is associated with Inborn genetic diseases (ClinVar).

How common is EXOSC3 p.Ala59Val (c.176C>T) in the general population?

EXOSC3 p.Ala59Val (c.176C>T) is very rare (popmax 0.00068%, nfe) (gnomAD).

What do computational predictors say about EXOSC3 p.Ala59Val (c.176C>T)?

AlphaMissense predicts likely benign (score 0.0809) — an in-silico prediction, not a clinical call.

EXOSC3 p.Ala59Val

c.176C>T · rs371853233 · VCV2230821

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0809 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00068%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0809	likely benign
REVEL	0.019	moderately benign-leaning
SaProt	LLR -7.15	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 0.44	GERP -1.6
Regional constraint	o/e 1.09	unconstrained · MANE · 4,362 bp · p 0.097 · regional, not allelic
Overall
CADD	6.773	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 0.00068% European (non-Finnish) · 8/1,177,096 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000622% 10/1,607,358 alleles · very rare exomes 10/1,454,988 · genomes 0/152,370 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0034%	29,388
Remaining individualsnot grpmax-eligible	0.00161%	62,198
European (non-Finnish)grpmax	0.00068%	147,137

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.Ala59Val
Coding: c.176C>T
MANE Select: NM_016042
dbSNP: rs371853233
Type: single nucleotide variant
Location: chr9:37784869 (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

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

Similar variants

EXOSC3 p.Ala2Val Uncertain significance ★★ ⚠ same condition
EXOSC3 p.Cys83Gly Uncertain significance ★★ ⚠ same condition
EXOSC3 p.Ser262Leu Uncertain significance ★★ ⚠ same condition
EXOSC3 p.Ser6Cys Uncertain significance ★★ ⚠ same condition
EXOSC3 p.Ser6Phe Uncertain significance ★★ ⚠ same condition
EXOSC3 p.Thr150Ala Uncertain significance ★★ ⚠ same condition
EXOSC3 p.Val131Ala Uncertain significance ★★ ⚠ same condition
EXOSC3 p.Val159Ala Uncertain significance ★★ ⚠ 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-ala59val (accessed [today's date]).

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