Is DVL1 p.Val669Phe (c.2005G>T) pathogenic?

DVL1 p.Val669Phe (c.2005G>T) is classified Conflicting classifications of pathogenicity in DVL1 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-01-26). AlphaMissense: likely benign (0.2832); Rare (popmax 0.183%, mid); Associated with autosomal dominant Robinow syndrome 2.

What condition is associated with DVL1 p.Val669Phe (c.2005G>T)?

DVL1 p.Val669Phe (c.2005G>T) is associated with autosomal dominant Robinow syndrome 2 (ClinVar).

How common is DVL1 p.Val669Phe (c.2005G>T) in the general population?

DVL1 p.Val669Phe (c.2005G>T) is rare (popmax 0.183%, mid) (gnomAD).

What do computational predictors say about DVL1 p.Val669Phe (c.2005G>T)?

AlphaMissense predicts likely benign (score 0.2832) — an in-silico prediction, not a clinical call.

DVL1 p.Val669Phe

c.2005G>T · rs374440563 · VCV1562503

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.2832 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.183%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autosomal dominant Robinow syndrome 2

Computational evidence

Protein change
AlphaMissense	0.2832	likely benign
REVEL	0.14	moderately benign-leaning
SaProt	LLR -7.54	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 2.2	GERP 0.26, phastCons 0.98
Regional constraint	o/e 1.15	unconstrained · MANE · 13 kb · p 2.8e-06 · regional, not allelic
Overall
CADD	17.81	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 0.183% Middle Eastern · 11/6,008 alleles

Filtering AF 0.103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0793%

Overall 0.0226% 352/1,557,432 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.183%	546
Admixed American	0.0899%	1,112
African / African-American	0.0795%	1,257
Remaining individualsnot grpmax-eligible	0.061%	1,640
European (non-Finnish)	0.0169%	5,903
Finnishnot grpmax-eligible	0.00208%	48,002

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: DVL1
Protein: p.Val669Phe
Coding: c.2005G>T
MANE Select: NM_001330311
dbSNP: rs374440563
Type: single nucleotide variant
Location: chr1:1336225 (GRCh38)
Gene constraint: LOEUF 1.046 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 60.70 · 3 PDB

Full DVL1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

autosomal dominant Robinow syndrome 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

DVL1 p.Val669= Likely benign ★★ same residue
DVL1 p.Val669Asp Uncertain significance ★ ⚠ same residue
DVL1 p.Val669Ile Uncertain significance ★ ⚠ same residue
DVL1 p.Ala288Val Uncertain significance ★★ ⚠ same condition
DVL1 p.Arg116Gln Uncertain significance ★★ ⚠ same condition
DVL1 p.Arg128Cys Uncertain significance ★★ ⚠ same condition
DVL1 p.Arg40Gly Uncertain significance ★★ ⚠ same condition
DVL1 p.Glu85Asp 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-val669phe (accessed [today's date]).

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