Is DLL1 p.Val709Ile (c.2125G>A) pathogenic?

DLL1 p.Val709Ile (c.2125G>A) is classified Likely benign in DLL1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-12-01). AlphaMissense: likely benign (0.1157); Ultra-rare (popmax 0.09%, sas); Associated with Inborn genetic diseases.

What condition is associated with DLL1 p.Val709Ile (c.2125G>A)?

DLL1 p.Val709Ile (c.2125G>A) is associated with Inborn genetic diseases (ClinVar).

How common is DLL1 p.Val709Ile (c.2125G>A) in the general population?

DLL1 p.Val709Ile (c.2125G>A) is ultra-rare (popmax 0.09%, sas) (gnomAD).

What do computational predictors say about DLL1 p.Val709Ile (c.2125G>A)?

AlphaMissense predicts likely benign (score 0.1157) — an in-silico prediction, not a clinical call.

DLL1 p.Val709Ile

c.2125G>A · rs558852722 · VCV2419959

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1157 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.09%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1157	likely benign
REVEL	0.41	indeterminate
SaProt	LLR -6.43	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 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	23.7	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 0.09% South Asian · 82/91,092 alleles

Filtering AF 0.0743% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0685%

Overall 0.00638% 103/1,614,178 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.09%	1,111
East Asian	0.00891%	11,220
Remaining individualsnot grpmax-eligible	0.0064%	15,626
Admixed American	0.005%	20,012
European (non-Finnish)	0.000847%	118,005

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.Val709Ile
Coding: c.2125G>A
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

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

Similar variants

DLL1 p.Val709Phe Uncertain significance ★★ ⚠ same residue
DLL1 p.Ala550Thr Uncertain significance ★★ ⚠ same condition
DLL1 p.Ala564Thr Uncertain significance ★★ ⚠ same condition
DLL1 p.Arg168His Uncertain significance ★★ ⚠ same condition
DLL1 p.Arg207Ser Uncertain significance ★★ ⚠ same condition
DLL1 p.Arg252Gln Uncertain significance ★★ ⚠ same condition
DLL1 p.Arg430Cys Uncertain significance ★★ ⚠ same condition
DLL1 p.Arg502Cys 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-val709ile (accessed [today's date]).

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