Is DVL1 p.Pro646Leu (c.1937C>T) pathogenic?

DVL1 p.Pro646Leu (c.1937C>T) is classified Likely benign in DVL1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-09). AlphaMissense: likely benign (0.0736); Ultra-rare (popmax 0.0255%, afr); Associated with Inborn genetic diseases.

What condition is associated with DVL1 p.Pro646Leu (c.1937C>T)?

DVL1 p.Pro646Leu (c.1937C>T) is associated with Inborn genetic diseases (ClinVar).

How common is DVL1 p.Pro646Leu (c.1937C>T) in the general population?

DVL1 p.Pro646Leu (c.1937C>T) is ultra-rare (popmax 0.0255%, afr) (gnomAD).

What do computational predictors say about DVL1 p.Pro646Leu (c.1937C>T)?

AlphaMissense predicts likely benign (score 0.0736) — an in-silico prediction, not a clinical call.

DVL1 p.Pro646Leu

c.1937C>T · rs562753230 · VCV1621206

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0736 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0255%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0736	likely benign
REVEL	0.095	moderately benign-leaning
SaProt	LLR -7.73	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 6.6	GERP 0.35, phastCons 1
Regional constraint	o/e 1.15	unconstrained · MANE · 13 kb · p 2.8e-06 · regional, not allelic
Overall
CADD	18.63	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 0.0255% African / African-American · 19/74,428 alleles

Filtering AF 0.0167% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0138%

Overall 0.00128% 20/1,563,162 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0255%	3,917
European (non-Finnish)	8.61e-05%	1,160,980

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.Pro646Leu
Coding: c.1937C>T
MANE Select: NM_001330311
dbSNP: rs562753230
Type: single nucleotide variant
Location: chr1:1336293 (GRCh38)
Gene constraint: LOEUF 1.046 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 60.70 · 3 PDB
Residue 646: 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.Pro646= 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
DVL1 p.Arg149Gln 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-pro646leu (accessed [today's date]).

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