Is DVL3 p.Arg220Gln (c.659G>A) pathogenic?

DVL3 p.Arg220Gln (c.659G>A) is classified Uncertain significance in DVL3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-07). AlphaMissense: ambiguous (0.5283); Very rare (popmax 0.000851%, nfe); Associated with Inborn genetic diseases.

What condition is associated with DVL3 p.Arg220Gln (c.659G>A)?

DVL3 p.Arg220Gln (c.659G>A) is associated with Inborn genetic diseases (ClinVar).

How common is DVL3 p.Arg220Gln (c.659G>A) in the general population?

DVL3 p.Arg220Gln (c.659G>A) is very rare (popmax 0.000851%, nfe) (gnomAD).

What do computational predictors say about DVL3 p.Arg220Gln (c.659G>A)?

AlphaMissense predicts ambiguous (score 0.5283) — an in-silico prediction, not a clinical call.

DVL3 p.Arg220Gln

c.659G>A · rs369391885 · VCV2964655

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5283 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000851%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5283	ambiguous
REVEL	0.201	benign-leaning
SaProt	LLR -11.74	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 12	GERP 1.5, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 11 kb · p 4e-06 · regional, not allelic
Overall
CADD	32.0	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

Grpmax group 0.000851% European (non-Finnish) · 10/1,175,460 alleles

Filtering AF 0.00043% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000314%

Overall 0.000623% 10/1,604,368 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: DVL3
Protein: p.Arg220Gln
Coding: c.659G>A
MANE Select: NM_004423
dbSNP: rs369391885
Type: single nucleotide variant
Location: chr3:184165172 (GRCh38)
Gene constraint: LOEUF 0.536 · pLI 0.70 (gnomAD)
Structure: AlphaFold pLDDT 59.50 · 9 PDB
Residue 220: the 'disordered' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

DVL3 p.Arg220Trp Uncertain significance ★ ⚠ same residue
DVL3 p.Ala359Thr Uncertain significance ★★ ⚠ same condition
DVL3 p.Ala565Val Uncertain significance ★★ ⚠ same condition
DVL3 p.Ala593Val Uncertain significance ★★ ⚠ same condition
DVL3 p.Ala629Thr Uncertain significance ★★ ⚠ same condition
DVL3 p.Arg145Gln Uncertain significance ★★ ⚠ same condition
DVL3 p.Arg157Gln Uncertain significance ★★ ⚠ same condition
DVL3 p.Arg166Trp Uncertain significance ★★ ⚠ same condition

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-arg220gln (accessed [today's date]).

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