Is DLL4 p.Arg334Cys (c.1000C>T) pathogenic?

DLL4 p.Arg334Cys (c.1000C>T) is classified Uncertain significance in DLL4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-31). AlphaMissense: ambiguous (0.5479); Very rare (popmax 0.00329%, sas).

How common is DLL4 p.Arg334Cys (c.1000C>T) in the general population?

DLL4 p.Arg334Cys (c.1000C>T) is very rare (popmax 0.00329%, sas) (gnomAD).

What do computational predictors say about DLL4 p.Arg334Cys (c.1000C>T)?

AlphaMissense predicts ambiguous (score 0.5479) — an in-silico prediction, not a clinical call.

DLL4 p.Arg334Cys

c.1000C>T · VCV4691192

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5479 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00329%, sas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5479	ambiguous
REVEL	0.16	moderately benign-leaning
SaProt	LLR -10.69	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.3	GERP 0.39, phastCons 1
Regional constraint	o/e 0.71	unconstrained · MANE · 3,465 bp · p 2.5e-11 · regional, not allelic
Overall
CADD	31.0	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 0.00329% South Asian · 3/91,050 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.00062% 10/1,613,398 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00329%	30,350
Admixed American	0.00167%	59,942
European (non-Finnish)	0.000509%	196,621

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.Arg334Cys
Coding: c.1000C>T
MANE Select: NM_019074
Type: single nucleotide variant
Location: chr15:40934697 (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.Arg334His 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-arg334cys (accessed [today's date]).

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