# NM_130797.4(DPP6):c.2252C>T (p.Ala751Val)

https://sugi.bio/variant/dpp6-p-ala751val

## Summary

**DPP6 p.Ala751Val (c.2252C>T)** is classified **Uncertain significance** in DPP6 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-29). AlphaMissense: likely benign (0.2725); Very rare (popmax 0.00223%, eas).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs370708312 · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.00223%, eas)

## For patients & families {#patients}

This is a change in the DPP6 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 | [DPP6](https://sugi.bio/atlas/gene/DPP6/) |
| Protein change (HGVS p.) | p.Ala751Val |
| Coding change (HGVS c.) | c.2252C>T |
| MANE Select transcript | [NM_130797](https://www.ncbi.nlm.nih.gov/nuccore/NM_130797) |
| dbSNP | [rs370708312](https://www.ncbi.nlm.nih.gov/snp/rs370708312/) |
| Variant type | single nucleotide variant |
| Location | chr7:154887682-154887682 (GRCh38) |
| ClinVar | [VCV2581441](https://www.ncbi.nlm.nih.gov/clinvar/variation/2581441/) |

**All HGVS expressions:** `NC_000007.13:g.154679392C>T`, `NC_000007.14:g.154887682C>T`, `NG_033878.2:g.1144697C>T`, `NM_001039350.3:c.2060C>T`, `NM_001290252.2:c.1931C>T`, `NM_001364497.2:c.2069C>T`, `NM_001364498.2:c.2069C>T`, `NM_001364499.2:c.2069C>T`, `NM_001364500.2:c.2069C>T`, `NM_001936.5:c.2066C>T`, `NM_130797.4:c.2252C>T`, `NR_157195.2:n.2632C>T`, `NR_157196.2:n.2406C>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** (0.2725)
- REVEL 0.273 (benign-leaning) — agrees with AlphaMissense
- SaProt LLR -7.935 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 7.423, GERP 1.43, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 24.7**. 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 0.83** across the covering region of the MANE Select transcript (154,052,821–154,892,477), spanning 839,656 bp. Chi-square p 1.6e-08. 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>G, Δ0.34 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 **0.00223%** (eas) · FAF95 0.000542% · FAF99 0.000428% · 1/44,866 in the highest group · 14/1,613,798 alleles overall — very rare (popmax 0.00223%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.00223% | 44,866 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,482 |
| European (non-Finnish) | 0.00102% | 98,309 |

*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}

**DPP6** population constraint: LOEUF 0.751, pLI 1.1525e-10, missense-Z 1.372; ClinGen dosage — haploinsufficiency 1/3, triplosensitivity 0/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **complex neurodevelopmental disorder** — Disputed (AD)

## Protein context {#protein}

Residue **751** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 87.41, 76% of residues very-high.

**8 experimental structure(s)** (PDB): [1XFD](https://www.rcsb.org/structure/1XFD), [7E87](https://www.rcsb.org/structure/7E87), [7E89](https://www.rcsb.org/structure/7E89), [7E8B](https://www.rcsb.org/structure/7E8B), [7E8E](https://www.rcsb.org/structure/7E8E), [7E8G](https://www.rcsb.org/structure/7E8G).

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

*Describes the biological roles of DPP6 (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:** DPP6's established molecular role includes potassium channel regulator activity.


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

**Molecular function:** potassium channel regulator activity.

**Biological process:** regulation of potassium ion transmembrane transport.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-08-29.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-08-29 |

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

## Similar variants {#similar}

Related DPP6 variant pages (same residue, condition, or type): [DPP6 p.Gly65Cys](/variant/dpp6-p-gly65cys), [DPP6 p.Gly65Val](/variant/dpp6-p-gly65val), [DPP6 p.Lys223Arg](/variant/dpp6-p-lys223arg), [DPP6 p.Pro229Thr](/variant/dpp6-p-pro229thr), [DPP6 c.1261-188G>A](/variant/dpp6-c-1261-minus-188g-a), [DPP6 c.1261-48G>A](/variant/dpp6-c-1261-minus-48g-a), [DPP6 c.1299+147A>G](/variant/dpp6-c-1299-plus-147a-g), [DPP6 c.1299+200A>G](/variant/dpp6-c-1299-plus-200a-g).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 2026-10-14); 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 2581441). 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.*