Is DLL3 p.Val328Phe (c.982G>T) pathogenic?

DLL3 p.Val328Phe (c.982G>T) is classified Conflicting classifications of pathogenicity in DLL3 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-12-03). AlphaMissense: likely benign (0.2353); Rare (popmax 0.13%, amr); Associated with syndactyly.

What condition is associated with DLL3 p.Val328Phe (c.982G>T)?

DLL3 p.Val328Phe (c.982G>T) is associated with syndactyly, spondylocostal dysostosis 1, autosomal recessive (ClinVar).

How common is DLL3 p.Val328Phe (c.982G>T) in the general population?

DLL3 p.Val328Phe (c.982G>T) is rare (popmax 0.13%, amr) (gnomAD).

What do computational predictors say about DLL3 p.Val328Phe (c.982G>T)?

AlphaMissense predicts likely benign (score 0.2353) — an in-silico prediction, not a clinical call.

DLL3 p.Val328Phe

c.982G>T · rs749513254 · VCV499140

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.2353 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.13%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

syndactyly

Computational evidence

Protein change
AlphaMissense	0.2353	likely benign
REVEL	0.54	indeterminate
SaProt	LLR -9.40	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	Δ0.36	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 8.3	GERP 1.5, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 9,279 bp · p 0.0035 · regional, not allelic
Overall
CADD	32.0	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 0.13% Admixed American · 78/59,998 alleles

Filtering AF 0.107% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0982%

Overall 0.00489% 79/1,614,082 alleles · rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.13%	769
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: DLL3
Protein: p.Val328Phe
Coding: c.982G>T
MANE Select: NM_203486
dbSNP: rs749513254
Type: single nucleotide variant
Location: chr19:39505340 (GRCh38)
Gene constraint: LOEUF 1.512 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.42
Residue 328: a disulfide bond; the egf-like 3 domain

Full DLL3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

syndactyly — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: spondylocostal dysostosis 1, autosomal recessive

Similar variants

DLL3 p.Val328= 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-val328phe (accessed [today's date]).

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