Is DLL1 p.Ala367Thr (c.1099G>A) pathogenic?

DLL1 p.Ala367Thr (c.1099G>A) is classified Uncertain significance in DLL1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-12-22). AlphaMissense: likely benign (0.2594); Very rare (popmax 0.00297%, nfe); Associated with neurodevelopmental disorder with nonspecific brain abnormalities and with or without seizures.

How common is DLL1 p.Ala367Thr (c.1099G>A) in the general population?

DLL1 p.Ala367Thr (c.1099G>A) is very rare (popmax 0.00297%, nfe) (gnomAD).

What do computational predictors say about DLL1 p.Ala367Thr (c.1099G>A)?

AlphaMissense predicts likely benign (score 0.2594) — an in-silico prediction, not a clinical call.

DLL1 p.Ala367Thr

Q: What condition is associated with DLL1 p.Ala367Thr (c.1099G>A)?

DLL1 p.Ala367Thr (c.1099G>A) is associated with neurodevelopmental disorder with nonspecific brain abnormalities and with or without seizures (ClinVar).

c.1099G>A · rs200985462 · VCV1925651

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2594 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00297%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

neurodevelopmental disorder with nonspecific brain abnormalities and with or without seizures

Computational evidence

Protein change
AlphaMissense	0.2594	likely benign
REVEL	0.578	indeterminate
SaProt	LLR -4.58	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 7.5	GERP -0.26, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 2,388 bp · p 0.59 · regional, not allelic
Overall
CADD	25.2	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 0.00297% European (non-Finnish) · 35/1,180,042 alleles

Filtering AF 0.00215% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00191%

Overall 0.00235% 38/1,614,042 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00297%	33,715
African / African-American	0.00267%	37,464
Remaining individualsnot grpmax-eligible	0.0016%	62,486

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.Ala367Thr
Coding: c.1099G>A
MANE Select: NM_005618
dbSNP: rs200985462
Type: single nucleotide variant
Location: chr6:170285069 (GRCh38)
Gene constraint: LOEUF 0.236 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.24 · 1 PDB
Residue 367: a UniProt-annotated variant site (in nedbas); a β-strand

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

Disease context

neurodevelopmental disorder with nonspecific brain abnormalities and with or without seizures — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

DLL1 p.Arg509Ter Pathogenic ★★ same condition
DLL1 c.413-3T>G Uncertain significance ★★ same condition
DLL1 p.Ala448Val Uncertain significance ★★ ⚠ same condition
DLL1 p.Ala550Thr Uncertain significance ★★ ⚠ same condition
DLL1 p.Arg176Cys Uncertain significance ★★ ⚠ same condition
DLL1 p.Arg392Cys Uncertain significance ★★ ⚠ same condition
DLL1 p.Arg430His Uncertain significance ★★ ⚠ same condition
DLL1 p.Arg635Cys 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-ala367thr (accessed [today's date]).

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