Is EXOSC5 p.Pro41Ser (c.121C>T) pathogenic?

EXOSC5 p.Pro41Ser (c.121C>T) is classified Uncertain significance in EXOSC5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-28). AlphaMissense: likely pathogenic (0.6451); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with EXOSC5 p.Pro41Ser (c.121C>T)?

EXOSC5 p.Pro41Ser (c.121C>T) is associated with Inborn genetic diseases (ClinVar).

How common is EXOSC5 p.Pro41Ser (c.121C>T) in the general population?

EXOSC5 p.Pro41Ser (c.121C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about EXOSC5 p.Pro41Ser (c.121C>T)?

AlphaMissense predicts likely pathogenic (score 0.6451) — an in-silico prediction, not a clinical call.

EXOSC5 p.Pro41Ser

c.121C>T · VCV4252037

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6451 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.6451	likely pathogenic
REVEL	0.288	benign-leaning
SaProt	LLR -5.95	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 11 kb · p 0.52 · regional, not allelic
Overall
CADD	24.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: EXOSC5
Protein: p.Pro41Ser
Coding: c.121C>T
MANE Select: NM_020158
Type: single nucleotide variant
Location: chr19:41397208 (GRCh38)
Gene constraint: LOEUF 1.136 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.59 · 8 PDB
Residue 41: a β-strand

Full EXOSC5 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

EXOSC5 p.Ala137Thr Uncertain significance ★★ ⚠ same condition
EXOSC5 p.Glu174Gly Uncertain significance ★★ same condition
EXOSC5 p.Thr17Ile Uncertain significance ★★ ⚠ same condition
EXOSC5 p.Ala104Val Uncertain significance ★ ⚠ same condition
EXOSC5 p.Ala150Thr Uncertain significance ★ ⚠ same condition
EXOSC5 p.Ala216Thr Uncertain significance ★ same condition
EXOSC5 p.Ala56Val Uncertain significance ★ ⚠ same condition
EXOSC5 p.Arg149Gln 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/exosc5-p-pro41ser (accessed [today's date]).

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