Is ARPP21 p.Pro447Arg (c.1340C>G) pathogenic?

ARPP21 p.Pro447Arg (c.1340C>G) is classified Uncertain significance in ARPP21 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-18). AlphaMissense: likely benign (0.1423); Ultra-rare (popmax 0.0156%, eas).

How common is ARPP21 p.Pro447Arg (c.1340C>G) in the general population?

ARPP21 p.Pro447Arg (c.1340C>G) is ultra-rare (popmax 0.0156%, eas) (gnomAD).

What do computational predictors say about ARPP21 p.Pro447Arg (c.1340C>G)?

AlphaMissense predicts likely benign (score 0.1423) — an in-silico prediction, not a clinical call.

ARPP21 p.Pro447Arg

c.1340C>G · VCV3948707

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1423 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0156%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1423	likely benign
REVEL	0.071	moderately benign-leaning
SaProt	LLR -7.04	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 4	phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 112 kb · p 0.31 · regional, not allelic
Overall
CADD	21.4	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 0.0156% East Asian · 7/44,868 alleles

Filtering AF 0.00726% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00515%

Overall 0.000434% 7/1,614,048 alleles · ultra-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: ARPP21
Protein: p.Pro447Arg
Coding: c.1340C>G
MANE Select: NM_001385562
Type: single nucleotide variant
Location: chr3:35729417 (GRCh38)
Gene constraint: LOEUF 0.711 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 52.34

Full ARPP21 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ARPP21 p.Pro563Leu Likely pathogenic ★ same type
ARPP21 p.Ala12Thr Uncertain significance ★ ⚠ same type
ARPP21 p.Ala179Thr Uncertain significance ★ ⚠ same type
ARPP21 p.Ala440Thr Uncertain significance ★ ⚠ same type
ARPP21 p.Ala498Val Uncertain significance ★ ⚠ same type
ARPP21 p.Ala708Gly Uncertain significance ★ ⚠ same type
ARPP21 p.Ala712Thr Uncertain significance ★ ⚠ same type
ARPP21 p.Ala829Val 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/arpp21-p-pro447arg (accessed [today's date]).

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