Is DLL1 p.Ser436Leu (c.1307C>T) pathogenic?

DLL1 p.Ser436Leu (c.1307C>T) is classified Uncertain significance in DLL1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-16). AlphaMissense: likely benign (0.1011); Ultra-rare (popmax 0.0261%, amr).

How common is DLL1 p.Ser436Leu (c.1307C>T) in the general population?

DLL1 p.Ser436Leu (c.1307C>T) is ultra-rare (popmax 0.0261%, amr) (gnomAD).

What do computational predictors say about DLL1 p.Ser436Leu (c.1307C>T)?

AlphaMissense predicts likely benign (score 0.1011) — an in-silico prediction, not a clinical call.

DLL1 p.Ser436Leu

c.1307C>T · rs774614063 · VCV2705785

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1011 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0261%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1011	likely benign
REVEL	0.238	benign-leaning
SaProt	LLR -8.46	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 2,388 bp · p 0.59 · regional, not allelic
Overall
CADD	26.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0261% Admixed American · 15/57,428 alleles

Filtering AF 0.016% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.013%

Overall 0.00769% 122/1,586,938 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0261%	3,829
Remaining individualsnot grpmax-eligible	0.0146%	6,845
European (non-Finnish)	0.0076%	13,161
East Asian	0.00688%	14,527
African / African-American	0.00538%	18,602
South Asian	0.00227%	43,993

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.Ser436Leu
Coding: c.1307C>T
MANE Select: NM_005618
dbSNP: rs774614063
Type: single nucleotide variant
Location: chr6:170283972 (GRCh38)
Gene constraint: LOEUF 0.236 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.24 · 1 PDB
Residue 436: the egf-like 6 domain; a disulfide bond; a UniProt-annotated variant site (in nedbas)

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

Similar variants

DLL1 p.Ser436= Likely benign ★★ same residue
DLL1 p.Arg509Ter Pathogenic ★★ same type
DLL1 c.413-3T>G Uncertain significance ★★ same type
DLL1 p.Ala367Thr Uncertain significance ★★ ⚠ same type
DLL1 p.Ala371Val Uncertain significance ★★ ⚠ same type
DLL1 p.Ala448Val Uncertain significance ★★ ⚠ same type
DLL1 p.Ala550Thr Uncertain significance ★★ ⚠ same type
DLL1 p.Ala564Thr Uncertain significance ★★ ⚠ same type

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-ser436leu (accessed [today's date]).

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