# NM_203486.3(DLL3):c.702C>T (p.Pro234=)

https://sugi.bio/variant/dll3-p-pro234

## Summary

**DLL3 p.Pro234= (c.702C>T)** is classified **Likely benign** in DLL3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-17). Very rare (popmax 0.00667%, amr).

**At a glance:** Likely benign · review: Single submitter · rsID rs1316480394 · 1 submitter · very rare (popmax 0.00667%, amr)

## For patients & families {#patients}

This is a change in the DLL3 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [DLL3](https://sugi.bio/atlas/gene/DLL3/) |
| Protein change (HGVS p.) | p.Pro234= |
| Coding change (HGVS c.) | c.702C>T |
| MANE Select transcript | [NM_203486](https://www.ncbi.nlm.nih.gov/nuccore/NM_203486) |
| dbSNP | [rs1316480394](https://www.ncbi.nlm.nih.gov/snp/rs1316480394/) |
| Variant type | single nucleotide variant |
| Location | chr19:39504120-39504120 (GRCh38) |
| ClinVar | [VCV720456](https://www.ncbi.nlm.nih.gov/clinvar/variation/720456/) |

**All HGVS expressions:** `NC_000019.10:g.39504120C>T`, `NC_000019.9:g.39994760C>T`, `NG_008256.1:g.10204C>T`, `NM_016941.4:c.702C>T`, `NM_203486.3:c.702C>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP -20, GERP -3.53 — fast-evolving / accelerated position
- CADD: **PHRED 0.362**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (C>A, Δ0.27 donor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00667%** (amr) · FAF95 0.00226% · FAF99 0.00135% · 4/60,010 in the highest group · 19/1,612,966 alleles overall — very rare (popmax 0.00667%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.008% | 12,496 |
| Admixed American (grpmax) | 0.00667% | 15,002 |
| South Asian | 0.0011% | 91,090 |
| European (non-Finnish) | 0.000763% | 131,113 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**DLL3** population constraint: LOEUF 1.512, pLI 3.0199e-20, missense-Z -3.403. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **234** lies in a disulfide bond; the egf-like 1 domain.

AlphaFold model confidence (whole protein): pLDDT 65.42, 7% of residues very-high.

## What this gene does {#gene-function}

*Describes the biological roles of DLL3 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*


### Pathways affected {#pathways}

DLL3 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Formation of paraxial mesoderm](https://reactome.org/content/detail/R-HSA-9793380) | other |
| [Somitogenesis](https://reactome.org/content/detail/R-HSA-9824272) | other |

### Molecular function & processes (GO — experimentally supported) {#go}

**Biological process:** skeletal system development.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-11-17.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2023-11-17 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related DLL3 variant pages (same residue, condition, or type): [DLL3 c.652+1G>T](/variant/dll3-c-652-plus-1g-t), [DLL3 p.Arg221Ter](/variant/dll3-p-arg221ter), [DLL3 p.Arg238Ter](/variant/dll3-p-arg238ter), [DLL3 p.Cys178Ter](/variant/dll3-p-cys178ter), [DLL3 p.Cys207Ter](/variant/dll3-p-cys207ter), [DLL3 p.Cys379Tyr](/variant/dll3-p-cys379tyr), [DLL3 p.Gln346Ter](/variant/dll3-p-gln346ter), [DLL3 p.Gly504Asp](/variant/dll3-p-gly504asp).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-07-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 720456). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*