Is DLL1 p.Arg259Cys (c.775C>T) pathogenic?

DLL1 p.Arg259Cys (c.775C>T) is classified Uncertain significance in DLL1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-10). AlphaMissense: likely pathogenic (0.7464); Very rare (popmax 0.00667%, afr); Associated with Inborn genetic diseases.

What condition is associated with DLL1 p.Arg259Cys (c.775C>T)?

DLL1 p.Arg259Cys (c.775C>T) is associated with Inborn genetic diseases (ClinVar).

How common is DLL1 p.Arg259Cys (c.775C>T) in the general population?

DLL1 p.Arg259Cys (c.775C>T) is very rare (popmax 0.00667%, afr) (gnomAD).

What do computational predictors say about DLL1 p.Arg259Cys (c.775C>T)?

AlphaMissense predicts likely pathogenic (score 0.7464) — an in-silico prediction, not a clinical call.

DLL1 p.Arg259Cys

c.775C>T · VCV3840396

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7464 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.7464	likely pathogenic
REVEL	0.339	indeterminate
SaProt	LLR -13.92	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.2	GERP 0.96, phastCons 1
Regional constraint	o/e 0.66	unconstrained · MANE · 4,873 bp · p 2e-13 · regional, not allelic
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00667% African / African-American · 5/74,918 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00161%

Overall 0.00136% 22/1,613,908 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00667%	14,984
Remaining individualsnot grpmax-eligible	0.0048%	20,829
European (non-Finnish)	0.00119%	84,288

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.Arg259Cys
Coding: c.775C>T
MANE Select: NM_005618
Type: single nucleotide variant
Location: chr6:170285656 (GRCh38)
Gene constraint: LOEUF 0.236 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.24 · 1 PDB
Residue 259: a disulfide bond; a UniProt-annotated variant site (in nedbas); the egf-like 2 domain

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.Arg259His Uncertain significance ★ same residue
DLL1 p.Arg259Leu 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

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-arg259cys (accessed [today's date]).

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