# NM_022355.4(DPEP2):c.103A>T (p.Thr35Ser)

https://sugi.bio/variant/dpep2-p-thr35ser

## Summary

**DPEP2 p.Thr35Ser (c.103A>T)** is classified **Uncertain significance** in DPEP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-03). AlphaMissense: likely benign (0.0943); Rare (popmax 0.182%, afr).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely benign · rare (popmax 0.182%, afr)

## For patients & families {#patients}

This is a change in the DPEP2 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 | [DPEP2](https://sugi.bio/atlas/gene/DPEP2/) |
| Protein change (HGVS p.) | p.Thr35Ser |
| Coding change (HGVS c.) | c.103A>T |
| MANE Select transcript | [NM_022355](https://www.ncbi.nlm.nih.gov/nuccore/NM_022355) |
| Variant type | single nucleotide variant |
| Location | chr16:67993110-67993110 (GRCh38) |
| ClinVar | [VCV4014514](https://www.ncbi.nlm.nih.gov/clinvar/variation/4014514/) |

**All HGVS expressions:** `NC_000016.10:g.67993110T>A`, `NC_000016.9:g.68027013T>A`, `NM_001324159.2:c.-84-917A>T`, `NM_001369657.1:c.103A>T`, `NM_022355.4:c.103A>T`, `NR_136706.2:n.802A>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** (0.0943)
- REVEL 0.027 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -8.473 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **acceptor gain** (Δ 0.29) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 0.045, GERP 0.291 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 17.2**. 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 0.96** across the covering region of the MANE Select transcript (67,987,509–67,993,212), spanning 5,703 bp. Chi-square p 0.27. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.29**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.29**, donor gain **0.00**.
- Pangolin: Δ**0.21** (gain), gain 0.21 / loss 0.00. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.182%** (afr) · FAF95 0.157% · FAF99 0.148% · 134/73,536 in the highest group · 148/1,564,126 alleles overall — rare (popmax 0.182%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.182% | 549 |
| Admixed American | 0.0153% | 6,528 |
| Remaining individuals (not grpmax-eligible) | 0.00827% | 12,097 |
| European (non-Finnish) | 8.67e-05% | 1,153,776 |

*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}

**DPEP2** population constraint: LOEUF 1.089, pLI 1.2437e-13, missense-Z 0.46639. *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 82.94, 70% of residues very-high.

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

*Describes the biological roles of DPEP2 (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:** DPEP2's established molecular role includes dipeptidase activity. In Reactome, DPEP2 is annotated in disease pathway(s) including **LTC4-CYSLTR mediated IL4 production**.

**Disease mechanism (Reactome):** DPEP2 loss or alteration is curated in [LTC4-CYSLTR mediated IL4 production](https://reactome.org/content/detail/R-HSA-9664535).

### Pathways affected {#pathways}

DPEP2 participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [LTC4-CYSLTR mediated IL4 production](https://reactome.org/content/detail/R-HSA-9664535) | curated |
| [Aflatoxin activation and detoxification](https://reactome.org/content/detail/R-HSA-5423646) | curated |
| [Synthesis of Leukotrienes (LT) and Eoxins (EX)](https://reactome.org/content/detail/R-HSA-2142691) | curated |

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

**Molecular function:** dipeptidase activity.

**Biological process:** leukotriene D4 catabolic process.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-04-03.

**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 | 2025-04-03 |

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

## Similar variants {#similar}

Related DPEP2 variant pages (same residue, condition, or type): [DPEP2 p.Ala226Thr](/variant/dpep2-p-ala226thr), [DPEP2 p.Ala276Thr](/variant/dpep2-p-ala276thr), [DPEP2 p.Ala33Thr](/variant/dpep2-p-ala33thr), [DPEP2 p.Ala59Thr](/variant/dpep2-p-ala59thr), [DPEP2 p.Ala78Val](/variant/dpep2-p-ala78val), [DPEP2 p.Arg147Cys](/variant/dpep2-p-arg147cys), [DPEP2 p.Arg147His](/variant/dpep2-p-arg147his), [DPEP2 p.Arg158Cys](/variant/dpep2-p-arg158cys).

### 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 4014514). 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.*