Is DLL4 p.Val69Phe (c.205G>T) pathogenic?

DLL4 p.Val69Phe (c.205G>T) is classified Conflicting classifications of pathogenicity in DLL4 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-03-16). AlphaMissense: likely benign (0.2101); Ultra-rare (popmax 0.0197%, nfe); Associated with Inborn genetic diseases.

What condition is associated with DLL4 p.Val69Phe (c.205G>T)?

DLL4 p.Val69Phe (c.205G>T) is associated with Inborn genetic diseases (ClinVar).

How common is DLL4 p.Val69Phe (c.205G>T) in the general population?

DLL4 p.Val69Phe (c.205G>T) is ultra-rare (popmax 0.0197%, nfe) (gnomAD).

What do computational predictors say about DLL4 p.Val69Phe (c.205G>T)?

AlphaMissense predicts likely benign (score 0.2101) — an in-silico prediction, not a clinical call.

DLL4 p.Val69Phe

c.205G>T · rs199931075 · VCV2357441

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.2101 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0197%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2101	likely benign
REVEL	0.332	indeterminate
SaProt	LLR -11.23	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 0.37	GERP -4.4, phastCons 0.048
Regional constraint	o/e 0.61	unconstrained · MANE · 2,750 bp · p 8.1e-14 · regional, not allelic
Overall
CADD	19.47	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 0.0197% European (non-Finnish) · 232/1,179,746 alleles

Filtering AF 0.0176% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0168%

Overall 0.0166% 268/1,612,934 alleles · ultra-rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0394%	2,536
European (non-Finnish)grpmax	0.0197%	5,085
Remaining individualsnot grpmax-eligible	0.0128%	7,803
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,572
African / African-American	0.00267%	37,465

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Val69Phe
Coding: c.205G>T
MANE Select: NM_019074
dbSNP: rs199931075
Type: single nucleotide variant
Location: chr15:40929985 (GRCh38)
Gene constraint: LOEUF 0.197 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 74.89 · 1 PDB
Residue 69: 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-val69phe (accessed [today's date]).

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