Is DLL3 p.Arg194Ser (c.580C>A) pathogenic?

DLL3 p.Arg194Ser (c.580C>A) is classified Uncertain significance in DLL3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-14). AlphaMissense: likely benign (0.1718); Absent from gnomAD v4.1.

How common is DLL3 p.Arg194Ser (c.580C>A) in the general population?

DLL3 p.Arg194Ser (c.580C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about DLL3 p.Arg194Ser (c.580C>A)?

AlphaMissense predicts likely benign (score 0.1718) — an in-silico prediction, not a clinical call.

DLL3 p.Arg194Ser

c.580C>A · rs1293083476 · VCV2053875

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1718 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,483,950)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1718	likely benign
REVEL	0.238	benign-leaning
SaProt	LLR -5.66	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 3.6	GERP 1.1, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 9,279 bp · p 0.0035 · regional, not allelic
Overall
CADD	22.0	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

No allele count reported in gnomAD v4.1 (AN 1,483,950). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: DLL3
Protein: p.Arg194Ser
Coding: c.580C>A
MANE Select: NM_203486
dbSNP: rs1293083476
Type: single nucleotide variant
Location: chr19:39502985 (GRCh38)
Gene constraint: LOEUF 1.512 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.42
Residue 194: the dsl domain

Full DLL3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DLL3 c.652+1G>T Likely pathogenic ★★ same type
DLL3 p.Arg221Ter Pathogenic ★★ same type
DLL3 p.Arg238Ter Pathogenic ★★ same type
DLL3 p.Cys178Ter Likely pathogenic ★★ same type
DLL3 p.Cys207Ter Pathogenic/Likely pathogenic ★★ same type
DLL3 p.Cys379Tyr Pathogenic/Likely pathogenic ★★ same type
DLL3 p.Gln346Ter Pathogenic/Likely pathogenic ★★ same type
DLL3 p.Gly504Asp Pathogenic/Likely pathogenic ★★ 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/dll3-p-arg194ser (accessed [today's date]).

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