Is DLL4 p.Ala67Val (c.200C>T) pathogenic?

DLL4 p.Ala67Val (c.200C>T) is classified Conflicting classifications of pathogenicity in DLL4 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-10-01). AlphaMissense: likely benign (0.1521); Ultra-rare (popmax 0.0571%, sas); Associated with Inborn genetic diseases.

What condition is associated with DLL4 p.Ala67Val (c.200C>T)?

DLL4 p.Ala67Val (c.200C>T) is associated with Inborn genetic diseases (ClinVar).

How common is DLL4 p.Ala67Val (c.200C>T) in the general population?

DLL4 p.Ala67Val (c.200C>T) is ultra-rare (popmax 0.0571%, sas) (gnomAD).

What do computational predictors say about DLL4 p.Ala67Val (c.200C>T)?

AlphaMissense predicts likely benign (score 0.1521) — an in-silico prediction, not a clinical call.

DLL4 p.Ala67Val

c.200C>T · rs534328045 · VCV1707857

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1521 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0571%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1521	likely benign
REVEL	0.313	indeterminate
SaProt	LLR -9.65	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	GERP 2.2, phastCons 1
Regional constraint	o/e 0.61	unconstrained · MANE · 2,750 bp · p 8.1e-14 · regional, not allelic
Overall
CADD	23.1	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 0.0571% South Asian · 52/91,044 alleles

Filtering AF 0.0447% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0403%

Overall 0.00341% 55/1,613,146 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0571%	1,751
Remaining individualsnot grpmax-eligible	0.0032%	31,227
Admixed American	0.00167%	59,972

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.Ala67Val
Coding: c.200C>T
MANE Select: NM_019074
dbSNP: rs534328045
Type: single nucleotide variant
Location: chr15:40929980 (GRCh38)
Gene constraint: LOEUF 0.197 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 74.89 · 1 PDB
Residue 67: a disulfide bond

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.Ala450Val Uncertain significance ★★ ⚠ same condition
DLL4 p.Arg186His Uncertain significance ★★ ⚠ same condition
DLL4 p.Arg313Cys 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-ala67val (accessed [today's date]).

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