Is DVL1 p.Arg376Cys (c.1126C>T) pathogenic?

DVL1 p.Arg376Cys (c.1126C>T) is classified Conflicting classifications of pathogenicity in DVL1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-05-14). AlphaMissense: likely benign (0.1063); Ultra-rare (popmax 0.0857%, mid); Associated with Inborn genetic diseases.

What condition is associated with DVL1 p.Arg376Cys (c.1126C>T)?

DVL1 p.Arg376Cys (c.1126C>T) is associated with Inborn genetic diseases (ClinVar).

How common is DVL1 p.Arg376Cys (c.1126C>T) in the general population?

DVL1 p.Arg376Cys (c.1126C>T) is ultra-rare (popmax 0.0857%, mid) (gnomAD).

What do computational predictors say about DVL1 p.Arg376Cys (c.1126C>T)?

AlphaMissense predicts likely benign (score 0.1063) — an in-silico prediction, not a clinical call.

DVL1 p.Arg376Cys

c.1126C>T · rs144499639 · VCV1035044

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1063 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0857%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1063	likely benign
REVEL	0.189	benign-leaning
SaProt	LLR -5.26	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.30 · evaluated, not missing
Constraint at this position
Conservation	phyloP 1.3	GERP -5.5, phastCons 0.002
Regional constraint	o/e 1.15	unconstrained · MANE · 13 kb · p 2.8e-06 · regional, not allelic
Overall
CADD	33.0	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 0.0857% Middle Eastern · 4/4,668 alleles

Filtering AF 0.0461% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.041%

Overall 0.00516% 80/1,548,890 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0857%	1,167
African / African-American	0.0602%	1,662
Remaining individualsnot grpmax-eligible	0.0167%	5,995
Admixed American	0.00784%	12,750
South Asian	0.00714%	14,000
European (non-Finnish)	0.00105%	95,573

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.Arg376Cys
Coding: c.1126C>T
MANE Select: NM_001330311
dbSNP: rs144499639
Type: single nucleotide variant
Location: chr1:1339368 (GRCh38)
Gene constraint: LOEUF 1.046 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 60.70 · 3 PDB

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.Ala125Val Uncertain significance ★★ ⚠ same condition
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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
DVL1 p.Arg150Cys 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-arg376cys (accessed [today's date]).

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