Is DLL4 p.Pro410Leu (c.1229C>T) pathogenic?

DLL4 p.Pro410Leu (c.1229C>T) is classified Uncertain significance in DLL4 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-09-09). AlphaMissense: likely benign (0.2408); Very rare (popmax 0.000339%, nfe).

How common is DLL4 p.Pro410Leu (c.1229C>T) in the general population?

DLL4 p.Pro410Leu (c.1229C>T) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about DLL4 p.Pro410Leu (c.1229C>T)?

AlphaMissense predicts likely benign (score 0.2408) — an in-silico prediction, not a clinical call.

DLL4 p.Pro410Leu

c.1229C>T · rs2140370935 · VCV1313181

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2408 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2408	likely benign
REVEL	0.48	indeterminate
SaProt	LLR -10.78	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	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	25.5	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 0.000339% European (non-Finnish) · 4/1,179,844 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000274% 4/1,459,954 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.Pro410Leu
Coding: c.1229C>T
MANE Select: NM_019074
dbSNP: rs2140370935
Type: single nucleotide variant
Location: chr15:40935106 (GRCh38)
Gene constraint: LOEUF 0.197 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 74.89 · 1 PDB
Residue 410: the egf-like 6 domain; a disulfide bond

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

Similar variants

DLL4 p.Cys390Tyr Pathogenic/Likely pathogenic ★★ same type
DLL4 p.Cys466Arg Likely pathogenic ★★ same type
DLL4 p.Gln584Ter Pathogenic/Likely pathogenic ★★ same type
DLL4 p.Ala450Val Uncertain significance ★★ ⚠ same type
DLL4 p.Arg186His Uncertain significance ★★ ⚠ same type
DLL4 p.Arg313Cys Uncertain significance ★★ ⚠ same type
DLL4 p.Arg645Gln Uncertain significance ★★ ⚠ same type
DLL4 p.Asn381Lys Uncertain significance ★★ ⚠ same type

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-pro410leu (accessed [today's date]).

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