Is DLL4 p.Arg558Ter (c.1672C>T) pathogenic?

DLL4 p.Arg558Ter (c.1672C>T) is classified Pathogenic in DLL4 (ClinVar, Single submitter, 2 submitters). Very rare (popmax 8.48e-05%, nfe); Associated with Adams-Oliver syndrome.

What condition is associated with DLL4 p.Arg558Ter (c.1672C>T)?

DLL4 p.Arg558Ter (c.1672C>T) is associated with Adams-Oliver syndrome, Adams-Oliver syndrome 6 (ClinVar).

How common is DLL4 p.Arg558Ter (c.1672C>T) in the general population?

DLL4 p.Arg558Ter (c.1672C>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

DLL4 p.Arg558Ter

c.1672C>T · rs61750844 · VCV204369

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Conditions

Adams-Oliver syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function in a LoF-intolerant gene
NMD	predicted	premature termination codon in exon 9 of 11
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.3	GERP 1.6, phastCons 1
Overall
CADD	37.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,798 alleles

Overall 6.85e-05% 1/1,459,988 alleles · very rare

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: DLL4
Protein: p.Arg558Ter
Coding: c.1672C>T
MANE Select: NM_019074
dbSNP: rs61750844
Type: single nucleotide variant
Location: chr15:40936659 (GRCh38)
Gene constraint: LOEUF 0.197 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 74.89 · 1 PDB

Full DLL4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Adams-Oliver syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Adams-Oliver syndrome 6

Similar variants

DLL4 p.Arg558Gln Uncertain significance ★ ⚠ same residue
DLL4 p.Cys390Tyr Pathogenic/Likely pathogenic ★★ same condition
DLL4 p.Cys466Arg Likely pathogenic ★★ same condition
DLL4 p.Gln584Ter Pathogenic/Likely pathogenic ★★ same condition
DLL4 c.1240+5G>A Likely pathogenic ★ same condition
DLL4 p.Ala121Pro Pathogenic ★ same condition
DLL4 p.Arg186Cys Pathogenic ★ same condition
DLL4 p.Cys390Arg 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/dll4-p-arg558ter (accessed [today's date]).

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