Is DVL3 p.Arg478His (c.1433G>A) pathogenic?

DVL3 p.Arg478His (c.1433G>A) is classified Uncertain significance in DVL3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-05). AlphaMissense: ambiguous (0.3942); Very rare (popmax 0.00223%, eas); Associated with Inborn genetic diseases.

What condition is associated with DVL3 p.Arg478His (c.1433G>A)?

DVL3 p.Arg478His (c.1433G>A) is associated with Inborn genetic diseases (ClinVar).

How common is DVL3 p.Arg478His (c.1433G>A) in the general population?

DVL3 p.Arg478His (c.1433G>A) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about DVL3 p.Arg478His (c.1433G>A)?

AlphaMissense predicts ambiguous (score 0.3942) — an in-silico prediction, not a clinical call.

DVL3 p.Arg478His

c.1433G>A · rs372843921 · VCV3250884

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3942 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3942	ambiguous
REVEL	0.642	indeterminate
SaProt	LLR -9.52	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.4, phastCons 1
Regional constraint	o/e 0.54	unconstrained · MANE · 1,228 bp · p 5.8e-11 · regional, not allelic
Overall
CADD	34.0	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 0.00223% East Asian · 1/44,882 alleles

Filtering AF 0.00103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00083%

Overall 0.00157% 23/1,461,886 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0048%	20,837
East Asiangrpmax	0.00223%	44,882
European (non-Finnish)	0.00161%	62,108

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg478His
Coding: c.1433G>A
MANE Select: NM_004423
dbSNP: rs372843921
Type: single nucleotide variant
Location: chr3:184168000 (GRCh38)
Gene constraint: LOEUF 0.536 · pLI 0.70 (gnomAD)
Structure: AlphaFold pLDDT 59.50 · 9 PDB
Residue 478: the dep domain

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.Arg478Cys 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-arg478his (accessed [today's date]).

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