# NM_012100.4(DNPEP):c.463C>T (p.Pro155Ser)

https://sugi.bio/variant/dnpep-p-pro155ser

## Summary

**DNPEP p.Pro155Ser (c.463C>T)** is classified **Uncertain significance** in DNPEP (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-16). AlphaMissense: likely benign (0.0815); Very rare (popmax 0.005%, amr).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs754619594 · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.005%, amr)

## For patients & families {#patients}

This is a change in the DNPEP gene that is currently of uncertain significance — a definitive interpretation has not yet been established, 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 | [DNPEP](https://sugi.bio/atlas/gene/DNPEP/) |
| Protein change (HGVS p.) | p.Pro155Ser |
| Coding change (HGVS c.) | c.463C>T |
| MANE Select transcript | [NM_012100](https://www.ncbi.nlm.nih.gov/nuccore/NM_012100) |
| dbSNP | [rs754619594](https://www.ncbi.nlm.nih.gov/snp/rs754619594/) |
| Variant type | single nucleotide variant |
| Location | chr2:219386095-219386095 (GRCh38) |
| ClinVar | [VCV2485525](https://www.ncbi.nlm.nih.gov/clinvar/variation/2485525/) |

**All HGVS expressions:** `NC_000002.11:g.220250817G>A`, `NC_000002.12:g.219386095G>A`, `NM_001319116.2:c.487C>T`, `NM_001319117.2:c.487C>T`, `NM_001319118.2:c.421C>T`, `NM_001319119.2:c.421C>T`, `NM_001319120.2:c.463C>T`, `NM_001319121.2:c.304C>T`, `NM_001319122.2:c.304C>T`, `NM_012100.4:c.463C>T`, `NR_134970.2:n.581C>T`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.0815)
- REVEL 0.051 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -8.307 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **acceptor gain** (Δ 0.27) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 9.703, GERP 1.44, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 21.9**. 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 0.95** across the covering region of the MANE Select transcript (219,374,295–219,387,794), spanning 13,499 bp. Chi-square p 0.2. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.03**, donor loss **0.00**, acceptor gain **0.27**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.27**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **0.005%** (amr) · FAF95 0.00199% · FAF99 0.00175% · 3/59,984 in the highest group · 36/1,613,888 alleles overall — very rare (popmax 0.005%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.005% | 19,995 |
| European (non-Finnish) | 0.0028% | 35,758 |

*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}

**DNPEP** population constraint: LOEUF 0.963, pLI 2.5859e-12, missense-Z 0.65214. *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 **155** lies in a turn.

AlphaFold model confidence (whole protein): pLDDT 95.95, 94% of residues very-high.

**1 experimental structure(s)** (PDB): [4DYO](https://www.rcsb.org/structure/4DYO).

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

*Describes the biological roles of DNPEP (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.*

**How this variant is thought to act:** DNPEP's established molecular role includes identical protein binding.


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

**Molecular function:** identical protein binding.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-02-16.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-02-16 |

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

## Similar variants {#similar}

Related DNPEP variant pages (same residue, condition, or type): [DNPEP p.Tyr308Cys](/variant/dnpep-p-tyr308cys), [DNPEP p.Ile171Val](/variant/dnpep-p-ile171val), [DNPEP p.Ala204Thr](/variant/dnpep-p-ala204thr), [DNPEP p.Ala221Thr](/variant/dnpep-p-ala221thr), [DNPEP p.Ala263Ser](/variant/dnpep-p-ala263ser), [DNPEP p.Ala27Val](/variant/dnpep-p-ala27val), [DNPEP p.Ala321Ser](/variant/dnpep-p-ala321ser), [DNPEP p.Arg114His](/variant/dnpep-p-arg114his).

### 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 2485525). 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.*