Is SENP3 p.Pro22Arg (c.65C>G) pathogenic?

SENP3 p.Pro22Arg (c.65C>G) is classified Uncertain significance in SENP3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-18). AlphaMissense: likely benign (0.1138); Very rare (popmax 0.00138%, afr).

How common is SENP3 p.Pro22Arg (c.65C>G) in the general population?

SENP3 p.Pro22Arg (c.65C>G) is very rare (popmax 0.00138%, afr) (gnomAD).

What do computational predictors say about SENP3 p.Pro22Arg (c.65C>G)?

AlphaMissense predicts likely benign (score 0.1138) — an in-silico prediction, not a clinical call.

SENP3 p.Pro22Arg

c.65C>G · VCV4582348

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1138 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00138%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1138	likely benign
REVEL	0.063	moderately benign-leaning
SaProt	LLR -6.38	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3.9	GERP 1.3, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 389 bp · p 0.76 · regional, not allelic
Overall
CADD	20.9	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 0.00138% African / African-American · 1/72,652 alleles

Overall 6.49e-05% 1/1,541,704 alleles · very rare exomes 1/1,389,430 · genomes 0/152,274 · 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: SENP3
Protein: p.Pro22Arg
Coding: c.65C>G
MANE Select: NM_015670
Type: single nucleotide variant
Location: chr17:7563141 (GRCh38)
Gene constraint: LOEUF 0.282 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 65.89 · 1 PDB
Residue 22: the 'disordered' region

Full SENP3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SENP3 p.Ala303Val Uncertain significance ★ ⚠ same type
SENP3 p.Ala382Ser Uncertain significance ★ ⚠ same type
SENP3 p.Ala74Thr Uncertain significance ★ ⚠ same type
SENP3 p.Arg101Gly Uncertain significance ★ ⚠ same type
SENP3 p.Arg134Trp Uncertain significance ★ ⚠ same type
SENP3 p.Arg157Gln Uncertain significance ★ ⚠ same type
SENP3 p.Arg210Gly Uncertain significance ★ ⚠ same type
SENP3 p.Arg310Gln 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/senp3-p-pro22arg (accessed [today's date]).

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