# NM_001935.4(DPP4):c.119G>A (p.Arg40His)

https://sugi.bio/variant/dpp4-p-arg40his

## Summary

**DPP4 p.Arg40His (c.119G>A)** is classified **Uncertain significance** in DPP4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-10). AlphaMissense: likely benign (0.2115); Ultra-rare (popmax 0.0139%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely benign · ultra-rare (popmax 0.0139%, nfe)

## 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.Arg40His |
| Coding change (HGVS c.) | c.119G>A |
| MANE Select transcript | [NM_001935](https://www.ncbi.nlm.nih.gov/nuccore/NM_001935) |
| Variant type | single nucleotide variant |
| Location | chr2:162047477-162047477 (GRCh38) |
| ClinVar | [VCV3504949](https://www.ncbi.nlm.nih.gov/clinvar/variation/3504949/) |

**All HGVS expressions:** `NC_000002.11:g.162903987C>T`, `NC_000002.12:g.162047477C>T`, `NM_001379604.1:c.116G>A`, `NM_001379605.1:c.113G>A`, `NM_001379606.1:c.119G>A`, `NM_001935.4:c.119G>A`, `NR_166822.1:n.350G>A`, `NR_166823.1:n.489G>A`, `NR_166824.1:n.353G>A`, `NR_166825.1:n.353G>A`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.2115)
- REVEL 0.399 (indeterminate)
- SaProt LLR -13.912 (damaging) — differs from AlphaMissense
- → **In-silico consensus:** SaProt calls this damaging; AlphaMissense does not; REVEL makes no call
- SpliceAI predicts **acceptor loss** (Δ 0.22) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 2.26, GERP 2.56, phastCons 0.999 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 21.0**. 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 deltas (raw): acceptor loss **0.22**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**. Largest is acceptor loss.
- SpliceAI deltas (masked): acceptor loss **0.22**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **0.0139%** (nfe) · FAF95 0.0122% · FAF99 0.0115% · 161/1,154,778 in the highest group · 196/1,575,798 alleles overall — ultra-rare (popmax 0.0139%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0297% | 3,372 |
| European (non-Finnish) (grpmax) | 0.0139% | 7,173 |
| Finnish (not grpmax-eligible) | 0.0115% | 8,677 |
| African / African-American | 0.00536% | 18,655 |
| South Asian | 0.00351% | 28,526 |
| Admixed American | 0.00336% | 29,774 |
| East Asian | 0.00226% | 44,336 |

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}

**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 **40** 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 2024-11-10.

**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 | 2024-11-10 |

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

## Similar variants {#similar}

Related DPP4 variant pages (same residue, condition, or type): [DPP4 p.Arg40Cys](/variant/dpp4-p-arg40cys), [DPP4 p.Arg40Ser](/variant/dpp4-p-arg40ser), [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).

### 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 3504949). 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.*