Is DLL4 p.Thr317Pro (c.949A>C) pathogenic?

DLL4 p.Thr317Pro (c.949A>C) is classified Likely pathogenic in DLL4 (ClinVar, Single submitter, 1 submitter; last evaluated 2017-12-01). AlphaMissense: likely pathogenic (0.6635); Absent from gnomAD v4.1; Associated with Adams-Oliver syndrome 6.

What condition is associated with DLL4 p.Thr317Pro (c.949A>C)?

DLL4 p.Thr317Pro (c.949A>C) is associated with Adams-Oliver syndrome 6 (ClinVar).

How common is DLL4 p.Thr317Pro (c.949A>C) in the general population?

DLL4 p.Thr317Pro (c.949A>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about DLL4 p.Thr317Pro (c.949A>C)?

AlphaMissense predicts likely pathogenic (score 0.6635) — an in-silico prediction, not a clinical call.

DLL4 p.Thr317Pro

c.949A>C · rs1555393027 · VCV523590

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6635 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Adams-Oliver syndrome 6

Computational evidence

Protein change
AlphaMissense	0.6635	likely pathogenic ✓ concordant with ClinVar
REVEL	0.763	pathogenic-leaning
SaProt	LLR -13.53	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.1	GERP 2.6, phastCons 1
Regional constraint	o/e 0.71	unconstrained · MANE · 3,465 bp · p 2.5e-11 · regional, not allelic
Overall
CADD	26.4	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: DLL4
Protein: p.Thr317Pro
Coding: c.949A>C
MANE Select: NM_019074
dbSNP: rs1555393027
Type: single nucleotide variant
Location: chr15:40934646 (GRCh38)
Gene constraint: LOEUF 0.197 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 74.89 · 1 PDB
Residue 317: a disulfide bond; the egf-like 3 domain; a β-strand

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

Disease context

Adams-Oliver syndrome 6 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

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.Arg558Ter 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-thr317pro (accessed [today's date]).

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