Is DVL3 p.Arg222Trp (c.664C>T) pathogenic?

DVL3 p.Arg222Trp (c.664C>T) is classified Uncertain significance in DVL3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-04-06). AlphaMissense: likely pathogenic (0.7805); Very rare (popmax 0.00223%, eas).

How common is DVL3 p.Arg222Trp (c.664C>T) in the general population?

DVL3 p.Arg222Trp (c.664C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about DVL3 p.Arg222Trp (c.664C>T)?

AlphaMissense predicts likely pathogenic (score 0.7805) — an in-silico prediction, not a clinical call.

DVL3 p.Arg222Trp

c.664C>T · rs774865679 · VCV2136193

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7805 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7805	likely pathogenic
REVEL	0.227	benign-leaning
SaProt	LLR -14.14	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.39 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.69	GERP 0.43, phastCons 0.98
Regional constraint	o/e 0.79	unconstrained · MANE · 11 kb · p 4e-06 · regional, not allelic
Overall
CADD	26.5	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 0.00223% East Asian · 1/44,790 alleles

Overall 0.000138% 2/1,450,160 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,790
Admixed American	0.00172%	58,002

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.Arg222Trp
Coding: c.664C>T
MANE Select: NM_004423
dbSNP: rs774865679
Type: single nucleotide variant
Location: chr3:184165177 (GRCh38)
Gene constraint: LOEUF 0.536 · pLI 0.70 (gnomAD)
Structure: AlphaFold pLDDT 59.50 · 9 PDB
Residue 222: the 'disordered' region

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

Similar variants

DVL3 p.Arg222dup Uncertain significance ★ same residue
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

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-arg222trp (accessed [today's date]).

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