Is DLL3 p.Pro206Ala (c.616C>G) pathogenic?

DLL3 p.Pro206Ala (c.616C>G) is classified Conflicting classifications of pathogenicity in DLL3 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-01-26). AlphaMissense: likely benign (0.0635); Low-frequency (popmax 1.04%, afr); Associated with Inborn genetic diseases.

What condition is associated with DLL3 p.Pro206Ala (c.616C>G)?

DLL3 p.Pro206Ala (c.616C>G) is associated with Inborn genetic diseases, spondylocostal dysostosis 1, autosomal recessive, syndactyly (ClinVar).

How common is DLL3 p.Pro206Ala (c.616C>G) in the general population?

DLL3 p.Pro206Ala (c.616C>G) is low-frequency (popmax 1.04%, afr) (gnomAD).

What do computational predictors say about DLL3 p.Pro206Ala (c.616C>G)?

AlphaMissense predicts likely benign (score 0.0635) — an in-silico prediction, not a clinical call.

DLL3 p.Pro206Ala

c.616C>G · rs376905666 · VCV501672

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.0635 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.04%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0635	likely benign
REVEL	0.241	benign-leaning
SaProt	LLR -6.49	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 2.9	GERP 1.1, phastCons 0.99
Regional constraint	o/e 1.10	unconstrained · MANE · 9,279 bp · p 0.0035 · regional, not allelic
Overall
CADD	19.23	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 1.04% African / African-American · 737/70,550 alleles

Filtering AF 0.982% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.957%

Overall 0.0574% 868/1,511,922 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.04%	96
Remaining individualsnot grpmax-eligible	0.0697%	1,434
Admixed American	0.0574%	1,741
Middle Eastern	0.0232%	4,304
East Asian	0.00526%	19,025
European (non-Finnish)	0.0051%	19,609
South Asian	0.00123%	81,470

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.Pro206Ala
Coding: c.616C>G
MANE Select: NM_203486
dbSNP: rs376905666
Type: single nucleotide variant
Location: chr19:39503021 (GRCh38)
Gene constraint: LOEUF 1.512 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.42
Residue 206: the dsl domain

Full DLL3 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

Also linked: spondylocostal dysostosis 1, autosomal recessive syndactyly

Similar variants

DLL3 p.Pro206fs Pathogenic ★★ same residue
DLL3 p.Pro206Ser Benign ★★ same residue
DLL3 p.Pro206= Likely benign ★ same residue
DLL3 c.652+1G>T Likely pathogenic ★★ same condition
DLL3 p.Arg238Ter Pathogenic ★★ same condition
DLL3 p.Cys178Ter Likely pathogenic ★★ same condition
DLL3 p.Cys207Ter Pathogenic/Likely pathogenic ★★ same condition
DLL3 p.Cys379Tyr Pathogenic/Likely pathogenic ★★ 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/dll3-p-pro206ala (accessed [today's date]).

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