Is DLL3 p.Pro343= (c.1029C>T) pathogenic?

DLL3 p.Pro343= (c.1029C>T) is classified Benign in DLL3 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-02-04). Common (popmax 38.4%, mid) — too common for a highly-penetrant pathogenic allele; Associated with syndactyly.

What condition is associated with DLL3 p.Pro343= (c.1029C>T)?

DLL3 p.Pro343= (c.1029C>T) is associated with syndactyly, spondylocostal dysostosis 1, autosomal recessive (ClinVar).

DLL3 p.Pro343=

Q: How common is DLL3 p.Pro343= (c.1029C>T) in the general population?

DLL3 p.Pro343= (c.1029C>T) is common (popmax 38.4%, mid) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1029C>T · rs2304214 · VCV260772

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Common

common (popmax 38.4%, mid) — too common for a highly-penetrant pathogenic allele

Conditions

syndactyly

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.82 · evaluated, not missing
Constraint at this position
Conservation	phyloP -12	GERP -3.7
Overall
CADD	1.836	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 38.4% Middle Eastern · 2,329/6,062 alleles

Filtering AF 37.1% ClinGen BA1/BS1 input FAF95, joint · FAF99 36.6%

Overall 31.9% 515,549/1,613,884 alleles · common

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	38.9%	3
Middle Easterngrpmax	38.4%	3
European (non-Finnish)	33.4%	3
South Asian	33.1%	3
Remaining individualsnot grpmax-eligible	31.4%	3
Amishnot grpmax-eligible	30.7%	3
Admixed American	30.1%	3
Ashkenazi Jewishnot grpmax-eligible	29.3%	3
African / African-American	17%	6
East Asian	11.5%	9

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro343=
Coding: c.1029C>T
MANE Select: NM_203486
dbSNP: rs2304214
Type: single nucleotide variant
Location: chr19:39505387 (GRCh38)
Gene constraint: LOEUF 1.512 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.42
Residue 343: a disulfide bond; the egf-like 3 domain

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-pro343 (accessed [today's date]).

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