Is DLL4 p.Arg313Cys (c.937C>T) pathogenic?

DLL4 p.Arg313Cys (c.937C>T) is classified Uncertain significance in DLL4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-08-10). AlphaMissense: ambiguous (0.3445); Very rare (popmax 0.004%, afr); Associated with Inborn genetic diseases.

What condition is associated with DLL4 p.Arg313Cys (c.937C>T)?

DLL4 p.Arg313Cys (c.937C>T) is associated with Inborn genetic diseases (ClinVar).

How common is DLL4 p.Arg313Cys (c.937C>T) in the general population?

DLL4 p.Arg313Cys (c.937C>T) is very rare (popmax 0.004%, afr) (gnomAD).

What do computational predictors say about DLL4 p.Arg313Cys (c.937C>T)?

AlphaMissense predicts ambiguous (score 0.3445) — an in-silico prediction, not a clinical call.

DLL4 p.Arg313Cys

c.937C>T · rs959903939 · VCV1503750

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3445 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.004%, afr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3445	ambiguous
REVEL	0.225	benign-leaning
SaProt	LLR -13.02	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 4.9	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	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 0.004% African / African-American · 3/74,936 alleles

Filtering AF 0.00122% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.0018% 29/1,613,814 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.004%	24,979
Admixed American	0.00333%	29,998
East Asian	0.00223%	44,896
European (non-Finnish)	0.00186%	53,631
South Asian	0.0011%	91,080

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.Arg313Cys
Coding: c.937C>T
MANE Select: NM_019074
dbSNP: rs959903939
Type: single nucleotide variant
Location: chr15:40934634 (GRCh38)
Gene constraint: LOEUF 0.197 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 74.89 · 1 PDB
Residue 313: a disulfide bond; the egf-like 3 domain

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

DLL4 p.Arg313His Conflicting classifications of pathogenicity ★ ⚠ same residue
DLL4 p.Ala450Val Uncertain significance ★★ ⚠ same condition
DLL4 p.Arg186His Uncertain significance ★★ ⚠ same condition
DLL4 p.Arg645Gln Uncertain significance ★★ ⚠ same condition
DLL4 p.Glu252Lys Uncertain significance ★★ ⚠ same condition
DLL4 p.His261Arg Uncertain significance ★★ ⚠ same condition
DLL4 p.Leu557Arg Uncertain significance ★★ ⚠ same condition
DLL4 p.Met547Thr Uncertain significance ★★ ⚠ 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-arg313cys (accessed [today's date]).

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