Is EXOSC3 p.Pro138Ser (c.412C>T) pathogenic?

EXOSC3 p.Pro138Ser (c.412C>T) is classified Uncertain significance in EXOSC3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-18). AlphaMissense: likely benign (0.1219); Very rare (popmax 0.000678%, nfe); Associated with Inborn genetic diseases.

What condition is associated with EXOSC3 p.Pro138Ser (c.412C>T)?

EXOSC3 p.Pro138Ser (c.412C>T) is associated with Inborn genetic diseases (ClinVar).

How common is EXOSC3 p.Pro138Ser (c.412C>T) in the general population?

EXOSC3 p.Pro138Ser (c.412C>T) is very rare (popmax 0.000678%, nfe) (gnomAD).

What do computational predictors say about EXOSC3 p.Pro138Ser (c.412C>T)?

AlphaMissense predicts likely benign (score 0.1219) — an in-silico prediction, not a clinical call.

EXOSC3 p.Pro138Ser

c.412C>T · rs1187569437 · VCV2271803

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1219 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000678%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1219	likely benign
REVEL	0.138	moderately benign-leaning
SaProt	LLR -9.46	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 8.4	GERP 1.6, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 4,362 bp · p 0.097 · regional, not allelic
Overall
CADD	24.4	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 0.000678% European (non-Finnish) · 8/1,179,952 alleles

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

Overall 0.000496% 8/1,613,784 alleles · very rare exomes 8/1,461,506 · genomes 0/152,278 · 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: EXOSC3
Protein: p.Pro138Ser
Coding: c.412C>T
MANE Select: NM_016042
dbSNP: rs1187569437
Type: single nucleotide variant
Location: chr9:37783976 (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.Pro138= Likely benign ★ same residue
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

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-pro138ser (accessed [today's date]).

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