Is EXOSC4 p.Pro191Ser (c.571C>T) pathogenic?

EXOSC4 p.Pro191Ser (c.571C>T) is classified Uncertain significance in EXOSC4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-24). AlphaMissense: ambiguous (0.5566); Very rare (popmax 0.00666%, afr).

How common is EXOSC4 p.Pro191Ser (c.571C>T) in the general population?

EXOSC4 p.Pro191Ser (c.571C>T) is very rare (popmax 0.00666%, afr) (gnomAD).

What do computational predictors say about EXOSC4 p.Pro191Ser (c.571C>T)?

AlphaMissense predicts ambiguous (score 0.5566) — an in-silico prediction, not a clinical call.

EXOSC4 p.Pro191Ser

c.571C>T · VCV3846841

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5566 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00666%, afr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5566	ambiguous
REVEL	0.275	benign-leaning
SaProt	LLR -11.61	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.8, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 1,869 bp · p 0.87 · regional, not allelic
Overall
CADD	27.1	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 0.00666% African / African-American · 5/75,042 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00161%

Overall 0.00328% 5/152,302 alleles · very rare

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: EXOSC4
Protein: p.Pro191Ser
Coding: c.571C>T
MANE Select: NM_019037
Type: single nucleotide variant
Location: chr8:144080434 (GRCh38)
Gene constraint: LOEUF 1.359 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.34 · 8 PDB
Residue 191: a turn

Full EXOSC4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EXOSC4 p.Gln75= Benign ★★ same type
EXOSC4 p.Ala159Val Uncertain significance ★ ⚠ same type
EXOSC4 p.Ala197Thr Uncertain significance ★ ⚠ same type
EXOSC4 p.Ala19Ser Uncertain significance ★ ⚠ same type
EXOSC4 p.Ala203Thr Uncertain significance ★ ⚠ same type
EXOSC4 p.Ala2Val Uncertain significance ★ ⚠ same type
EXOSC4 p.Arg118His Uncertain significance ★ ⚠ same type
EXOSC4 p.Arg204Gln Uncertain significance ★ same type

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/exosc4-p-pro191ser (accessed [today's date]).

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