Is DVL1 p.Pro657fs (c.1968dup) pathogenic?

DVL1 p.Pro657fs (c.1968dup) is classified Uncertain significance in DVL1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-07). Very rare (popmax 0.00347%, sas).

How common is DVL1 p.Pro657fs (c.1968dup) in the general population?

DVL1 p.Pro657fs (c.1968dup) is very rare (popmax 0.00347%, sas) (gnomAD).

DVL1 p.Pro657fs

c.1968dup · rs756990609 · VCV1053244

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00347%, sas)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (15 of 15) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 11	GERP 1.5, phastCons 1
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00347% South Asian · 3/86,354 alleles

Filtering AF 0.000923% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000661%

Overall 0.00128% 20/1,559,574 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00347%	28,785
Admixed American	0.00187%	53,452
European (non-Finnish)	0.00138%	72,442

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.Pro657fs
Coding: c.1968dup
MANE Select: NM_001330311
dbSNP: rs756990609
Type: Duplication
Location: chr1:1336261 (GRCh38)
Gene constraint: LOEUF 1.046 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 60.70 · 3 PDB
Residue 657: the 'disordered' region

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

Similar variants

DVL1 p.Ser562fs Likely pathogenic ★ same type
DVL1 p.Val445fs Likely pathogenic ★ same type
DVL1 c.1683_1714+6dup Uncertain significance ★ same type
DVL1 p.Arg617fs Uncertain significance ★ same type
DVL1 p.Ser559fs Uncertain significance ★ same type
DVL1 p.Val349dup Uncertain significance ★ same type
DVL1 c.1208-25_1208-15dup Likely benign ★ same type
DVL1 c.606-17dup Likely benign ★ 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/dvl1-p-pro657fs (accessed [today's date]).

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