Is DLL3 p.Ala96Thr (c.286G>A) pathogenic?

DLL3 p.Ala96Thr (c.286G>A) is classified Uncertain significance in DLL3 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-03-18). AlphaMissense: likely benign (0.081); Ultra-rare (popmax 0.0176%, nfe); Associated with Inborn genetic diseases.

What condition is associated with DLL3 p.Ala96Thr (c.286G>A)?

DLL3 p.Ala96Thr (c.286G>A) is associated with Inborn genetic diseases, spondylocostal dysostosis 1, autosomal recessive (ClinVar).

How common is DLL3 p.Ala96Thr (c.286G>A) in the general population?

DLL3 p.Ala96Thr (c.286G>A) is ultra-rare (popmax 0.0176%, nfe) (gnomAD).

What do computational predictors say about DLL3 p.Ala96Thr (c.286G>A)?

AlphaMissense predicts likely benign (score 0.081) — an in-silico prediction, not a clinical call.

DLL3 p.Ala96Thr

c.286G>A · rs546600885 · VCV1483838

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.081 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0176%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.081	likely benign
REVEL	0.099	moderately benign-leaning
SaProt	LLR -8.18	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 1.8	GERP -0.054, phastCons 0.008
Regional constraint	o/e 1.10	unconstrained · MANE · 9,279 bp · p 0.0035 · regional, not allelic
Overall
CADD	14.24	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 0.0176% European (non-Finnish) · 206/1,173,304 alleles

Filtering AF 0.0155% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0148%

Overall 0.0136% 216/1,584,986 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0176%	5,696
Remaining individualsnot grpmax-eligible	0.0113%	8,821
African / African-American	0.00268%	37,286
Admixed American	0.00171%	58,342

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: DLL3
Protein: p.Ala96Thr
Coding: c.286G>A
MANE Select: NM_203486
dbSNP: rs546600885
Type: single nucleotide variant
Location: chr19:39499408 (GRCh38)
Gene constraint: LOEUF 1.512 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.42

Full DLL3 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

Also linked: spondylocostal dysostosis 1, autosomal recessive

Similar variants

DLL3 p.Ala96Glu Uncertain significance ★★ ⚠ same residue
DLL3 c.652+1G>T Likely pathogenic ★★ same condition
DLL3 p.Arg238Ter Pathogenic ★★ same condition
DLL3 p.Cys178Ter Likely pathogenic ★★ same condition
DLL3 p.Cys207Ter Pathogenic/Likely pathogenic ★★ same condition
DLL3 p.Cys379Tyr Pathogenic/Likely pathogenic ★★ same condition
DLL3 p.Gln346Ter Pathogenic/Likely pathogenic ★★ same condition
DLL3 p.Gly504Asp Pathogenic/Likely pathogenic ★★ 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/dll3-p-ala96thr (accessed [today's date]).

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