Is DLL3 p.Ile34Phe (c.100A>T) pathogenic?

DLL3 p.Ile34Phe (c.100A>T) is classified Uncertain significance in DLL3 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-14). AlphaMissense: ambiguous (0.4823); Ultra-rare (popmax 0.0187%, nfe); Associated with Inborn genetic diseases.

What condition is associated with DLL3 p.Ile34Phe (c.100A>T)?

DLL3 p.Ile34Phe (c.100A>T) is associated with Inborn genetic diseases, spondylocostal dysostosis 1, autosomal recessive, syndactyly (ClinVar).

How common is DLL3 p.Ile34Phe (c.100A>T) in the general population?

DLL3 p.Ile34Phe (c.100A>T) is ultra-rare (popmax 0.0187%, nfe) (gnomAD).

What do computational predictors say about DLL3 p.Ile34Phe (c.100A>T)?

AlphaMissense predicts ambiguous (score 0.4823) — an in-silico prediction, not a clinical call.

DLL3 p.Ile34Phe

c.100A>T · rs781688970 · VCV893094

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.4823 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0187%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4823	ambiguous
REVEL	0.702	pathogenic-leaning
SaProt	LLR -8.51	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 0.95, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 9,279 bp · p 0.0035 · regional, not allelic
Overall
CADD	24.9	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 0.0187% European (non-Finnish) · 217/1,158,276 alleles

Filtering AF 0.0167% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0159%

Overall 0.0142% 221/1,560,512 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0187%	5,338
African / African-American	0.00272%	36,777
Finnishnot grpmax-eligible	0.00195%	51,410
South Asian	0.00115%	86,836

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.Ile34Phe
Coding: c.100A>T
MANE Select: NM_203486
dbSNP: rs781688970
Type: single nucleotide variant
Location: chr19:39499222 (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 syndactyly

Similar variants

DLL3 p.Ile34= Likely benign ★ 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-ile34phe (accessed [today's date]).

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