Is DVL3 p.Pro591Arg (c.1772C>G) pathogenic?

DVL3 p.Pro591Arg (c.1772C>G) is classified Uncertain significance in DVL3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-06). AlphaMissense: likely benign (0.1161); Ultra-rare (popmax 0.0136%, amr).

How common is DVL3 p.Pro591Arg (c.1772C>G) in the general population?

DVL3 p.Pro591Arg (c.1772C>G) is ultra-rare (popmax 0.0136%, amr) (gnomAD).

What do computational predictors say about DVL3 p.Pro591Arg (c.1772C>G)?

AlphaMissense predicts likely benign (score 0.1161) — an in-silico prediction, not a clinical call.

DVL3 p.Pro591Arg

c.1772C>G · rs754383852 · VCV1512528

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1161 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0136%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1161	likely benign
REVEL	0.037	moderately benign-leaning
SaProt	LLR -5.07	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 2.1	GERP -0.61, phastCons 0.89
Regional constraint	o/e 0.98	unconstrained · MANE · 2,688 bp · p 0.69 · regional, not allelic
Overall
CADD	15.6	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 0.0136% Admixed American · 8/58,888 alleles

Filtering AF 0.00683% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00634%

Overall 0.00673% 108/1,605,582 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0136%	7,361
European (non-Finnish)	0.00816%	12,255
Remaining individualsnot grpmax-eligible	0.00322%	31,026
Finnishnot grpmax-eligible	0.0032%	31,221

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: DVL3
Protein: p.Pro591Arg
Coding: c.1772C>G
MANE Select: NM_004423
dbSNP: rs754383852
Type: single nucleotide variant
Location: chr3:184170376 (GRCh38)
Gene constraint: LOEUF 0.536 · pLI 0.70 (gnomAD)
Structure: AlphaFold pLDDT 59.50 · 9 PDB
Residue 591: the 'disordered' region

Full DVL3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DVL3 c.1715-1G>A Pathogenic/Likely pathogenic ★★ same type
DVL3 p.Ala359Thr Uncertain significance ★★ ⚠ same type
DVL3 p.Ala565Val Uncertain significance ★★ ⚠ same type
DVL3 p.Ala593Val Uncertain significance ★★ ⚠ same type
DVL3 p.Ala629Thr Uncertain significance ★★ ⚠ same type
DVL3 p.Arg145Gln Uncertain significance ★★ ⚠ same type
DVL3 p.Arg157Gln Uncertain significance ★★ ⚠ same type
DVL3 p.Arg166Trp 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/dvl3-p-pro591arg (accessed [today's date]).

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