Is EXOSC4 p.Pro67Arg (c.200C>G) pathogenic?

EXOSC4 p.Pro67Arg (c.200C>G) is classified Uncertain significance in EXOSC4 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-29). AlphaMissense: likely benign (0.2664); Absent from gnomAD v4.1.

How common is EXOSC4 p.Pro67Arg (c.200C>G) in the general population?

EXOSC4 p.Pro67Arg (c.200C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about EXOSC4 p.Pro67Arg (c.200C>G)?

AlphaMissense predicts likely benign (score 0.2664) — an in-silico prediction, not a clinical call.

EXOSC4 p.Pro67Arg

c.200C>G · rs1312749221 · VCV2258456

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2664 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2664	likely benign
REVEL	0.114	moderately benign-leaning
SaProt	LLR -10.48	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.6, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 1,869 bp · p 0.87 · regional, not allelic
Overall
CADD	23.0	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: EXOSC4
Protein: p.Pro67Arg
Coding: c.200C>G
MANE Select: NM_019037
dbSNP: rs1312749221
Type: single nucleotide variant
Location: chr8:144079971 (GRCh38)
Gene constraint: LOEUF 1.359 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.34 · 8 PDB
Residue 67: a β-strand

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-pro67arg (accessed [today's date]).

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