Is DLL3 p.Arg387Ser (c.1159C>A) pathogenic?

DLL3 p.Arg387Ser (c.1159C>A) is classified Uncertain significance in DLL3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-04). AlphaMissense: ambiguous (0.3749); Very rare (popmax 0.00136%, afr).

How common is DLL3 p.Arg387Ser (c.1159C>A) in the general population?

DLL3 p.Arg387Ser (c.1159C>A) is very rare (popmax 0.00136%, afr) (gnomAD).

What do computational predictors say about DLL3 p.Arg387Ser (c.1159C>A)?

AlphaMissense predicts ambiguous (score 0.3749) — an in-silico prediction, not a clinical call.

DLL3 p.Arg387Ser

c.1159C>A · VCV4942250

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3749 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00136%, afr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3749	ambiguous
REVEL	0.664	pathogenic-leaning
SaProt	LLR -8.89	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.2	GERP 1.8, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 9,279 bp · p 0.0035 · regional, not allelic
Overall
CADD	23.7	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 0.00136% African / African-American · 1/73,466 alleles

Overall 0.000144% 2/1,391,056 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00136%	73,466
European (non-Finnish)	8.68e-05%	1,151,822

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.Arg387Ser
Coding: c.1159C>A
MANE Select: NM_203486
Type: single nucleotide variant
Location: chr19:39507104 (GRCh38)
Gene constraint: LOEUF 1.512 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.42
Residue 387: a disulfide bond; the egf-like 4 domain

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

Similar variants

DLL3 p.Arg387Cys Uncertain significance ★★ ⚠ same residue
DLL3 p.Arg387= Likely benign ★ same residue
DLL3 p.Arg387fs Pathogenic ★ 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

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-arg387ser (accessed [today's date]).

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