Is DLL3 p.Ser173Pro (c.517T>C) pathogenic?

DLL3 p.Ser173Pro (c.517T>C) is classified Uncertain significance in DLL3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-23). AlphaMissense: likely pathogenic (0.8241); Very rare (popmax 0.00275%, amr).

How common is DLL3 p.Ser173Pro (c.517T>C) in the general population?

DLL3 p.Ser173Pro (c.517T>C) is very rare (popmax 0.00275%, amr) (gnomAD).

What do computational predictors say about DLL3 p.Ser173Pro (c.517T>C)?

AlphaMissense predicts likely pathogenic (score 0.8241) — an in-silico prediction, not a clinical call.

DLL3 p.Ser173Pro

c.517T>C · rs962122621 · VCV3251782

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8241 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00275%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.8241	likely pathogenic
REVEL	0.425	indeterminate
SaProt	LLR -12.53	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.7	GERP 1.4, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 9,279 bp · p 0.0035 · regional, not allelic
Overall
CADD	25.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Grpmax group 0.00275% Admixed American · 1/36,386 alleles

Overall 0.000208% 3/1,441,712 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00275%	36,386
Remaining individualsnot grpmax-eligible	0.00181%	55,242
European (non-Finnish)	9.06e-05%	1,103,470

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.Ser173Pro
Coding: c.517T>C
MANE Select: NM_203486
dbSNP: rs962122621
Type: single nucleotide variant
Location: chr19:39502922 (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.Ser173Trp Uncertain significance ★★ ⚠ same residue
DLL3 p.Ser173= Likely benign ★ 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

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-ser173pro (accessed [today's date]).

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