Is DLL4 p.Arg334His (c.1001G>A) pathogenic?

DLL4 p.Arg334His (c.1001G>A) is classified Uncertain significance in DLL4 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-22). AlphaMissense: likely benign (0.1302); Very rare (popmax 0.00659%, sas).

How common is DLL4 p.Arg334His (c.1001G>A) in the general population?

DLL4 p.Arg334His (c.1001G>A) is very rare (popmax 0.00659%, sas) (gnomAD).

What do computational predictors say about DLL4 p.Arg334His (c.1001G>A)?

AlphaMissense predicts likely benign (score 0.1302) — an in-silico prediction, not a clinical call.

DLL4 p.Arg334His

c.1001G>A · rs781059377 · VCV1437535

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1302 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00659%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1302	likely benign
REVEL	0.195	benign-leaning
SaProt	LLR -7.11	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.6	GERP 1.6, phastCons 1
Regional constraint	o/e 0.71	unconstrained · MANE · 3,465 bp · p 2.5e-11 · regional, not allelic
Overall
CADD	27.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00659% South Asian · 6/91,066 alleles

Filtering AF 0.00286% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00195%

Overall 0.00136% 22/1,613,474 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00659%	15,178
African / African-American	0.00534%	18,721
East Asian	0.00223%	44,870
Remaining individualsnot grpmax-eligible	0.0016%	62,454
European (non-Finnish)	0.000848%	117,973

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.Arg334His
Coding: c.1001G>A
MANE Select: NM_019074
dbSNP: rs781059377
Type: single nucleotide variant
Location: chr15:40934698 (GRCh38)
Gene constraint: LOEUF 0.197 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 74.89 · 1 PDB
Residue 334: a disulfide bond; the egf-like 4 domain

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

Similar variants

DLL4 p.Arg334Cys Uncertain significance ★ ⚠ same residue
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

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-arg334his (accessed [today's date]).

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