# NM_199286.4(DPPA3):c.169T>C (p.Ser57Pro)

https://sugi.bio/variant/dppa3-p-ser57pro

## Summary

**DPPA3 p.Ser57Pro (c.169T>C)** is classified **Likely benign** in DPPA3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-01). AlphaMissense: likely benign (0.045); Very rare (popmax 0.0011%, sas).

**At a glance:** Likely benign · review: Single submitter · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.0011%, sas)

## For patients & families {#patients}

This is a change in the DPPA3 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 | [DPPA3](https://sugi.bio/atlas/gene/DPPA3/) |
| Protein change (HGVS p.) | p.Ser57Pro |
| Coding change (HGVS c.) | c.169T>C |
| MANE Select transcript | [NM_199286](https://www.ncbi.nlm.nih.gov/nuccore/NM_199286) |
| Variant type | single nucleotide variant |
| Location | chr12:7715269-7715269 (GRCh38) |
| ClinVar | [VCV3842318](https://www.ncbi.nlm.nih.gov/clinvar/variation/3842318/) |

**All HGVS expressions:** `NC_000012.11:g.7867865T>C`, `NC_000012.12:g.7715269T>C`, `NM_199286.4:c.169T>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.045)
- REVEL 0.032 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.04 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP -0.313, GERP -2.4 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 0.229**. 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.*
- Regional missense constraint: **o/e 0.76** across the covering region of the MANE Select transcript (7,711,571–7,717,074), spanning 5,503 bp. Chi-square p 0.00084. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (T>G, Δ0.42 acceptor 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 **0.0011%** (sas) · FAF95 6.8e-05% · FAF99 1.9e-05% · 1/91,064 in the highest group · 4/1,461,678 alleles overall — very rare (popmax 0.0011%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.0011% | 91,064 |
| European (non-Finnish) | 0.000254% | 393,286 |

*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}

**DPPA3** population constraint: LOEUF 1.113, pLI 0.0083259, missense-Z 1.1018. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 63.46, 0% of residues very-high.

**3 experimental structure(s)** (PDB): [8WMS](https://www.rcsb.org/structure/8WMS), [8XV7](https://www.rcsb.org/structure/8XV7), [8XV8](https://www.rcsb.org/structure/8XV8).

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

*Describes the biological roles of DPPA3 (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}

DPPA3 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Chromatin modifications during the maternal to zygotic transition (MZT)](https://reactome.org/content/detail/R-HSA-9821002) | electronic |

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-01-01.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2025-01-01 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related DPPA3 variant pages (same residue, condition, or type): [DPPA3 p.Ala147Val](/variant/dppa3-p-ala147val), [DPPA3 p.Arg108Cys](/variant/dppa3-p-arg108cys), [DPPA3 p.Arg24Trp](/variant/dppa3-p-arg24trp), [DPPA3 p.Arg62Gly](/variant/dppa3-p-arg62gly), [DPPA3 p.Arg83Gly](/variant/dppa3-p-arg83gly), [DPPA3 p.Arg98Ser](/variant/dppa3-p-arg98ser), [DPPA3 p.Asn116Asp](/variant/dppa3-p-asn116asp), [DPPA3 p.Asn151Ser](/variant/dppa3-p-asn151ser).

### 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 3842318). 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.*