Is DVL1 p.Arg227Cys (c.679C>T) pathogenic?

DVL1 p.Arg227Cys (c.679C>T) is classified Conflicting classifications of pathogenicity in DVL1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-12-22). AlphaMissense: likely benign (0.2267); Ultra-rare (popmax 0.0495%, mid); Associated with Inborn genetic diseases.

What condition is associated with DVL1 p.Arg227Cys (c.679C>T)?

DVL1 p.Arg227Cys (c.679C>T) is associated with Inborn genetic diseases (ClinVar).

How common is DVL1 p.Arg227Cys (c.679C>T) in the general population?

DVL1 p.Arg227Cys (c.679C>T) is ultra-rare (popmax 0.0495%, mid) (gnomAD).

What do computational predictors say about DVL1 p.Arg227Cys (c.679C>T)?

AlphaMissense predicts likely benign (score 0.2267) — an in-silico prediction, not a clinical call.

DVL1 p.Arg227Cys

c.679C>T · rs747373290 · VCV1504972

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2267 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0495%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2267	likely benign
REVEL	0.103	moderately benign-leaning
SaProt	LLR -12.93	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.3	GERP -2.8, phastCons 0.92
Regional constraint	o/e 1.15	unconstrained · MANE · 13 kb · p 2.8e-06 · regional, not allelic
Overall
CADD	33.0	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 0.0495% Middle Eastern · 3/6,056 alleles

Filtering AF 0.0134% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00719%

Overall 0.00178% 26/1,460,084 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0495%	2,019
Remaining individualsnot grpmax-eligible	0.00481%	20,798
Finnishnot grpmax-eligible	0.00472%	21,199
European (non-Finnish)	0.00144%	69,380

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: DVL1
Protein: p.Arg227Cys
Coding: c.679C>T
MANE Select: NM_001330311
dbSNP: rs747373290
Type: single nucleotide variant
Location: chr1:1340430 (GRCh38)
Gene constraint: LOEUF 1.046 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 60.70 · 3 PDB
Residue 227: the 'disordered' region

Full DVL1 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

DVL1 p.Arg227His Uncertain significance ★ ⚠ same residue
DVL1 p.Arg227= Likely benign ★ same residue
DVL1 p.Ala125Val Uncertain significance ★★ ⚠ same condition
DVL1 p.Ala288Val Uncertain significance ★★ ⚠ same condition
DVL1 p.Ala361Thr Uncertain significance ★★ ⚠ same condition
DVL1 p.Ala368Val Uncertain significance ★★ ⚠ same condition
DVL1 p.Ala667Pro Uncertain significance ★★ ⚠ same condition
DVL1 p.Arg108Trp 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/dvl1-p-arg227cys (accessed [today's date]).

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