Is DVL2 p.Pro656Ser (c.1966C>T) pathogenic?

DVL2 p.Pro656Ser (c.1966C>T) is classified Uncertain significance in DVL2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-19). AlphaMissense: likely benign (0.068); Rare (popmax 0.168%, eas).

How common is DVL2 p.Pro656Ser (c.1966C>T) in the general population?

DVL2 p.Pro656Ser (c.1966C>T) is rare (popmax 0.168%, eas) (gnomAD).

What do computational predictors say about DVL2 p.Pro656Ser (c.1966C>T)?

AlphaMissense predicts likely benign (score 0.068) — an in-silico prediction, not a clinical call.

DVL2 p.Pro656Ser

c.1966C>T · VCV4662627

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.068 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.168%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.068	likely benign
REVEL	0.04	moderately benign-leaning
SaProt	LLR -6.78	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 3.8	GERP 1.1, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 1,247 bp · p 0.99 · regional, not allelic
Overall
CADD	14.96	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.168% East Asian · 75/44,702 alleles

Filtering AF 0.137% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.126%

Overall 0.00564% 90/1,596,916 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.168%	596
Remaining individualsnot grpmax-eligible	0.0162%	6,161
African / African-American	0.00537%	18,622
South Asian	0.00112%	89,376

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: DVL2
Protein: p.Pro656Ser
Coding: c.1966C>T
MANE Select: NM_004422
Type: single nucleotide variant
Location: chr17:7226110 (GRCh38)
Gene constraint: LOEUF 0.719 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 59.37 · 16 PDB
Residue 656: the 'disordered' region

Full DVL2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DVL2 c.1035-8C>T Benign ★★ same type
DVL2 c.1544-16T>C Benign ★★ same type
DVL2 p.Gln554= Benign ★★ same type
DVL2 p.Leu317= Benign ★★ same type
DVL2 p.Ser207= Benign ★★ same type
DVL2 p.Thr250= Likely benign ★★ same type
DVL2 p.Ala114Val Uncertain significance ★ ⚠ same type
DVL2 p.Ala384Val 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/dvl2-p-pro656ser (accessed [today's date]).

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