Is DLL3 p.Pro541= (c.1623G>A) pathogenic?

DLL3 p.Pro541= (c.1623G>A) is classified Conflicting classifications of pathogenicity in DLL3 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-12-15). Ultra-rare (popmax 0.0366%, nfe); Associated with syndactyly.

What condition is associated with DLL3 p.Pro541= (c.1623G>A)?

DLL3 p.Pro541= (c.1623G>A) is associated with syndactyly, spondylocostal dysostosis 1, autosomal recessive (ClinVar).

How common is DLL3 p.Pro541= (c.1623G>A) in the general population?

DLL3 p.Pro541= (c.1623G>A) is ultra-rare (popmax 0.0366%, nfe) (gnomAD).

DLL3 p.Pro541=

c.1623G>A · rs200988915 · VCV711080

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0366%, nfe)

Conditions

syndactyly

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -12	GERP -2.6
Overall
CADD	0.748	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0366% European (non-Finnish) · 431/1,178,250 alleles

Filtering AF 0.0337% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0325%

Overall 0.0278% 448/1,608,856 alleles · ultra-rare exomes 430/1,456,542 · genomes 18/152,314 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0366%	2,734
Admixed American	0.0101%	9,917
Remaining individualsnot grpmax-eligible	0.00963%	10,380
African / African-American	0.00534%	18,737
Finnishnot grpmax-eligible	0.0016%	62,566

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.Pro541=
Coding: c.1623G>A
MANE Select: NM_203486
dbSNP: rs200988915
Type: single nucleotide variant
Location: chr19:39507568 (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

Disease context

syndactyly — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: spondylocostal dysostosis 1, autosomal recessive

Similar variants

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
DLL3 p.Gln346Ter Pathogenic/Likely pathogenic ★★ same condition
DLL3 p.Gly504Asp Pathogenic/Likely pathogenic ★★ same condition
DLL3 c.1758+20C>G Uncertain significance ★★ ⚠ 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-pro541 (accessed [today's date]).

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