Is DVL2 p.Ser135= (c.405C>T) pathogenic?

DVL2 p.Ser135= (c.405C>T) is classified Benign in DVL2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-10-21). Common (popmax 39.8%, sas) — too common for a highly-penetrant pathogenic allele; Associated with DVL2-related disorder.

What condition is associated with DVL2 p.Ser135= (c.405C>T)?

DVL2 p.Ser135= (c.405C>T) is associated with DVL2-related disorder (ClinVar).

DVL2 p.Ser135=

Q: How common is DVL2 p.Ser135= (c.405C>T) in the general population?

DVL2 p.Ser135= (c.405C>T) is common (popmax 39.8%, sas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.405C>T · rs2074216 · VCV3060815

Benign No assertion criteria

Classification

Benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Common

common (popmax 39.8%, sas) — too common for a highly-penetrant pathogenic allele

Conditions

DVL2-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.19	GERP -3, phastCons 0.79
Overall
CADD	6.43	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 39.8% South Asian · 36,202/91,066 alleles

Filtering AF 39.4% ClinGen BA1/BS1 input FAF95, joint · FAF99 39.3%

Overall 35.8% 577,655/1,613,762 alleles · common exomes 526,336/1,461,836 · genomes 51,319/151,926 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	42.3%	2
South Asiangrpmax	39.8%	3
Middle Eastern	38.8%	3
Ashkenazi Jewishnot grpmax-eligible	38.2%	3
European (non-Finnish)	36.4%	3
Remaining individualsnot grpmax-eligible	36.1%	3
East Asian	35.5%	3
Amishnot grpmax-eligible	33%	3
African / African-American	26.7%	4
Admixed American	21.5%	5

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ser135=
Coding: c.405C>T
MANE Select: NM_004422
dbSNP: rs2074216
Type: single nucleotide variant
Location: chr17:7230290 (GRCh38)
Gene constraint: LOEUF 0.719 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 59.37 · 16 PDB
Residue 135: the 'disordered' region

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

Disease context

DVL2-related disorder

Similar variants

DVL2 c.410+10T>C Benign same condition
DVL2 c.656+8T>G Likely benign same condition
DVL2 c.748-8C>T Likely benign same condition
DVL2 c.-4G>C Likely benign same condition
DVL2 p.Ala111Val Likely benign same condition
DVL2 p.Arg77His Likely benign ⚠ same condition
DVL2 p.Glu193= Likely benign same condition
DVL2 p.Gly8= Likely benign 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/dvl2-p-ser135 (accessed [today's date]).

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