Is DLL3 p.Cys438Ser (c.1312T>A) pathogenic?

DLL3 p.Cys438Ser (c.1312T>A) is classified Likely pathogenic in DLL3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-23). AlphaMissense: likely pathogenic (0.9794); Very rare (popmax 0.00839%, sas); Associated with spondylocostal dysostosis 1, autosomal recessive.

What condition is associated with DLL3 p.Cys438Ser (c.1312T>A)?

DLL3 p.Cys438Ser (c.1312T>A) is associated with spondylocostal dysostosis 1, autosomal recessive (ClinVar).

How common is DLL3 p.Cys438Ser (c.1312T>A) in the general population?

DLL3 p.Cys438Ser (c.1312T>A) is very rare (popmax 0.00839%, sas) (gnomAD).

What do computational predictors say about DLL3 p.Cys438Ser (c.1312T>A)?

AlphaMissense predicts likely pathogenic (score 0.9794) — an in-silico prediction, not a clinical call.

DLL3 p.Cys438Ser

c.1312T>A · rs888371213 · VCV2572235

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9794 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00839%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

spondylocostal dysostosis 1, autosomal recessive

Computational evidence

Protein change
AlphaMissense	0.9794	likely pathogenic ✓ concordant with ClinVar · top 3% in DLL3
REVEL	0.974	strongly pathogenic-leaning
SaProt	LLR -13.87	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.3	GERP -0.42, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 9,279 bp · p 0.0035 · regional, not allelic
Overall
CADD	25.2	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 0.00839% South Asian · 7/83,420 alleles

Filtering AF 0.00388% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00274%

Overall 0.000458% 7/1,526,758 alleles · very rare

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.Cys438Ser
Coding: c.1312T>A
MANE Select: NM_203486
dbSNP: rs888371213
Type: single nucleotide variant
Location: chr19:39507257 (GRCh38)
Gene constraint: LOEUF 1.512 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.42
Residue 438: the egf-like 6 domain; a disulfide bond

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

Disease context

spondylocostal dysostosis 1, autosomal recessive — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

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
DLL3 c.1758+20C>G 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/dll3-p-cys438ser (accessed [today's date]).

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