Is DLL3 p.Arg57Ser (c.169C>A) pathogenic?

DLL3 p.Arg57Ser (c.169C>A) is classified Uncertain significance in DLL3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-14). AlphaMissense: ambiguous (0.4902); Very rare (popmax 0.000958%, nfe).

How common is DLL3 p.Arg57Ser (c.169C>A) in the general population?

DLL3 p.Arg57Ser (c.169C>A) is very rare (popmax 0.000958%, nfe) (gnomAD).

What do computational predictors say about DLL3 p.Arg57Ser (c.169C>A)?

AlphaMissense predicts ambiguous (score 0.4902) — an in-silico prediction, not a clinical call.

DLL3 p.Arg57Ser

c.169C>A · rs1441217676 · VCV1985496

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4902 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000958%, nfe)

Computational evidence

Protein change
AlphaMissense	0.4902	ambiguous
REVEL	0.574	indeterminate
SaProt	LLR -8.70	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 0.95, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 9,279 bp · p 0.0035 · regional, not allelic
Overall
CADD	29.3	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 0.000958% European (non-Finnish) · 11/1,148,168 alleles

Filtering AF 0.000514% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000376%

Overall 0.000791% 11/1,390,062 alleles · very rare

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: DLL3
Protein: p.Arg57Ser
Coding: c.169C>A
MANE Select: NM_203486
dbSNP: rs1441217676
Type: single nucleotide variant
Location: chr19:39499291 (GRCh38)
Gene constraint: LOEUF 1.512 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.42

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

Similar variants

DLL3 p.Arg57Gly Uncertain significance ★ ⚠ same residue
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

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-arg57ser (accessed [today's date]).

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