# NM_001935.4(DPP4):c.406G>C (p.Asp136His)

https://sugi.bio/variant/dpp4-p-asp136his

## Summary

**DPP4 p.Asp136His (c.406G>C)** is classified **Uncertain significance** in DPP4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-19). AlphaMissense: ambiguous (0.3966); Very rare (popmax 0.00769%, sas).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense ambiguous · very rare (popmax 0.00769%, sas)

## For patients & families {#patients}

This is a change in the DPP4 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 | [DPP4](https://sugi.bio/atlas/gene/DPP4/) |
| Protein change (HGVS p.) | p.Asp136His |
| Coding change (HGVS c.) | c.406G>C |
| MANE Select transcript | [NM_001935](https://www.ncbi.nlm.nih.gov/nuccore/NM_001935) |
| Variant type | single nucleotide variant |
| Location | chr2:162039145-162039145 (GRCh38) |
| ClinVar | [VCV3842274](https://www.ncbi.nlm.nih.gov/clinvar/variation/3842274/) |

**All HGVS expressions:** `NC_000002.11:g.162895655C>G`, `NC_000002.12:g.162039145C>G`, `NM_001379604.1:c.403G>C`, `NM_001379605.1:c.400G>C`, `NM_001379606.1:c.406G>C`, `NM_001935.4:c.406G>C`, `NR_166822.1:n.637G>C`, `NR_166823.1:n.880G>C`, `NR_166824.1:n.640G>C`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense makes no call; REVEL and SaProt both call this damaging; AlphaMissense makes no call — descriptive only.

- AlphaMissense **ambiguous** (0.3966) — no call either way
- REVEL 0.953 (strongly pathogenic-leaning)
- SaProt LLR -13.768 (damaging)
- → **In-silico consensus:** REVEL and SaProt both call this damaging; AlphaMissense makes no call
- Conservation: phyloP 3.277, GERP 1.8, phastCons 1 — highly conserved
- CADD: **PHRED 27.3**. 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 1.01** across the covering region of the MANE Select transcript (161,993,286–162,073,981), spanning 80,695 bp. Chi-square p 0.82. 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 (C>A, Δ0.20 acceptor loss), 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 **0.00769%** (sas) · FAF95 0.00359% · FAF99 0.00255% · 7/91,050 in the highest group · 7/1,460,702 alleles overall — very rare (popmax 0.00769%, sas).

*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}

**DPP4** population constraint: LOEUF 0.901, pLI 1.6454e-17, missense-Z 0.6449. *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 **136** lies in a β-strand.

AlphaFold model confidence (whole protein): pLDDT 96.45, 94% of residues very-high.

**121 experimental structure(s)** (PDB): [1J2E](https://www.rcsb.org/structure/1J2E), [1N1M](https://www.rcsb.org/structure/1N1M), [1NU6](https://www.rcsb.org/structure/1NU6), [1NU8](https://www.rcsb.org/structure/1NU8), [1PFQ](https://www.rcsb.org/structure/1PFQ), [1R9M](https://www.rcsb.org/structure/1R9M) — incl. mutant structure 1U8E.

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

*Describes the biological roles of DPP4 (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:** DPP4's established molecular role includes virus receptor activity.


### Pathways affected {#pathways}

DPP4 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1)](https://reactome.org/content/detail/R-HSA-381771) | curated |
| [Synthesis, secretion, and inactivation of Glucose-dependent Insulinotropic Polypeptide (GIP)](https://reactome.org/content/detail/R-HSA-400511) | curated |

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

**Molecular function:** virus receptor activity, protease binding, serine-type endopeptidase activity, signaling receptor binding, serine-type peptidase activity, dipeptidyl-peptidase activity.

**Biological process:** response to hypoxia, proteolysis, positive regulation of cell population proliferation, negative regulation of extracellular matrix disassembly, T cell costimulation, regulation of cell-cell adhesion mediated by integrin.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-02-19.

**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 | 2025-02-19 |

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

## Similar variants {#similar}

Related DPP4 variant pages (same residue, condition, or type): [DPP4 c.1987+4T>C](/variant/dpp4-c-1987-plus-4t-c), [DPP4 p.Ala16=](/variant/dpp4-p-ala16), [DPP4 p.Gly645=](/variant/dpp4-p-gly645), [DPP4 p.Leu27=](/variant/dpp4-p-leu27), [DPP4 p.Lys539=](/variant/dpp4-p-lys539), [DPP4 p.Ser437Thr](/variant/dpp4-p-ser437thr), [DPP4 p.Val266Ile](/variant/dpp4-p-val266ile), [DPP4 p.Ala654Thr](/variant/dpp4-p-ala654thr).

### 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 3842274). 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.*