Is DVL2 p.Pro366Leu (c.1097C>T) pathogenic?

DVL2 p.Pro366Leu (c.1097C>T) is classified Uncertain significance in DVL2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-12). AlphaMissense: likely pathogenic (0.7811); Very rare (popmax 0.00135%, afr).

How common is DVL2 p.Pro366Leu (c.1097C>T) in the general population?

DVL2 p.Pro366Leu (c.1097C>T) is very rare (popmax 0.00135%, afr) (gnomAD).

What do computational predictors say about DVL2 p.Pro366Leu (c.1097C>T)?

AlphaMissense predicts likely pathogenic (score 0.7811) — an in-silico prediction, not a clinical call.

DVL2 p.Pro366Leu

c.1097C>T · VCV4245660

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7811 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00135%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.7811	likely pathogenic
REVEL	0.384	indeterminate
SaProt	LLR -13.54	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 2.3, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 6,783 bp · p 0.16 · regional, not allelic
Overall
CADD	29.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00135% African / African-American · 1/73,940 alleles

Filtering AF 0.000625% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000482%

Overall 0.00089% 14/1,573,572 alleles · very rare exomes 13/1,421,398 · genomes 1/152,174 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00135%	73,940
European (non-Finnish)	0.00112%	89,228

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.Pro366Leu
Coding: c.1097C>T
MANE Select: NM_004422
Type: single nucleotide variant
Location: chr17:7227982 (GRCh38)
Gene constraint: LOEUF 0.719 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 59.37 · 16 PDB

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-pro366leu (accessed [today's date]).

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