Is DLL1 p.Val709Phe (c.2125G>T) pathogenic?

DLL1 p.Val709Phe (c.2125G>T) is classified Uncertain significance in DLL1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-07-22). AlphaMissense: ambiguous (0.4407); Very rare (popmax 0.00133%, afr); Associated with DLL1-related disorder.

What condition is associated with DLL1 p.Val709Phe (c.2125G>T)?

DLL1 p.Val709Phe (c.2125G>T) is associated with DLL1-related disorder (ClinVar).

How common is DLL1 p.Val709Phe (c.2125G>T) in the general population?

DLL1 p.Val709Phe (c.2125G>T) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about DLL1 p.Val709Phe (c.2125G>T)?

AlphaMissense predicts ambiguous (score 0.4407) — an in-silico prediction, not a clinical call.

DLL1 p.Val709Phe

c.2125G>T · rs558852722 · VCV2637114

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4407 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

DLL1-related disorder

Computational evidence

Protein change
AlphaMissense	0.4407	ambiguous
REVEL	0.65	pathogenic-leaning
SaProt	LLR -6.84	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.7, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 2,388 bp · p 0.59 · regional, not allelic
Overall
CADD	26.5	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 0.00133% African / African-American · 1/75,056 alleles

Overall 6.84e-05% 1/1,461,816 alleles · very rare

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: DLL1
Protein: p.Val709Phe
Coding: c.2125G>T
MANE Select: NM_005618
dbSNP: rs558852722
Type: single nucleotide variant
Location: chr6:170283029 (GRCh38)
Gene constraint: LOEUF 0.236 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.24 · 1 PDB
Residue 709: a UniProt-annotated variant site (in nedbas); a UniProt-annotated variant site (in nedbas; uncertain significance)

Full DLL1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

DLL1-related disorder

Similar variants

DLL1 p.Val709Ile Likely benign ★★ same residue
DLL1 p.Gly475Asp Uncertain significance ★★ ⚠ same condition
DLL1 p.Pro95Ser Uncertain significance ★★ ⚠ same condition
DLL1 p.Gln270Ter Likely pathogenic ★ same condition
DLL1 p.Pro261Leu Uncertain significance ★ ⚠ same condition
DLL1 p.Thr587Met Conflicting classifications of pathogenicity ★ ⚠ same condition
DLL1 p.Cys325Ter Likely pathogenic same condition
DLL1 p.Gly669Ala 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/dll1-p-val709phe (accessed [today's date]).

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