# NM_015954.4(DERA):c.860G>C (p.Arg287Pro)

https://sugi.bio/variant/dera-p-arg287pro

## Summary

**DERA p.Arg287Pro (c.860G>C)** is classified **Uncertain significance** in DERA (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-08). AlphaMissense: likely pathogenic (0.9933); Very rare (popmax 0.00195%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely pathogenic · very rare (popmax 0.00195%, nfe)

## For patients & families {#patients}

This is a change in the DERA 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 | [DERA](https://sugi.bio/atlas/gene/DERA/) |
| Protein change (HGVS p.) | p.Arg287Pro |
| Coding change (HGVS c.) | c.860G>C |
| MANE Select transcript | [NM_015954](https://www.ncbi.nlm.nih.gov/nuccore/NM_015954) |
| Variant type | single nucleotide variant |
| Location | chr12:16036341-16036341 (GRCh38) |
| ClinVar | [VCV4659636](https://www.ncbi.nlm.nih.gov/clinvar/variation/4659636/) |

**All HGVS expressions:** `NC_000012.11:g.16189275G>C`, `NC_000012.12:g.16036341G>C`, `NM_001300779.2:c.731G>C`, `NM_015954.4:c.860G>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.9933)
- REVEL 0.874 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -16.505 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- SpliceAI predicts **acceptor gain** (Δ 0.26) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 11.873, GERP 2.16, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 1%** most-pathogenic-predicted substitutions in DERA (of 1,851 modeled).
- CADD: **PHRED 35.0**. 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 0.98** across the covering region of the MANE Select transcript (15,911,384–16,036,743), spanning 125,359 bp. Chi-square p 0.71. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.08**, donor loss **0.01**, acceptor gain **0.26**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.01**, acceptor gain **0.26**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **0.00195%** (nfe) · FAF95 0.0013% · FAF99 0.00108% · 23/1,179,640 in the highest group · 27/1,613,308 alleles overall — very rare (popmax 0.00195%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0048% | 20,813 |
| European (non-Finnish) (grpmax) | 0.00195% | 51,289 |
| African / African-American | 0.00134% | 74,894 |

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}

**DERA** population constraint: LOEUF 0.658, pLI 0.34069, missense-Z -0.16005. *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 95.99, 93% of residues very-high.

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

*Describes the biological roles of DERA (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:** DERA's established molecular role includes deoxyribose-phosphate aldolase activity.


### Pathways affected {#pathways}

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

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Neutrophil degranulation](https://reactome.org/content/detail/R-HSA-6798695) | curated |
| [Pentose phosphate pathway](https://reactome.org/content/detail/R-HSA-71336) | curated |

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

**Molecular function:** deoxyribose-phosphate aldolase activity.

**Biological process:** 2'-deoxyribonucleoside catabolic process.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-12-08.

**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 | 2025-12-08 |

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

## Similar variants {#similar}

Related DERA variant pages (same residue, condition, or type): [DERA p.Ala115Ser](/variant/dera-p-ala115ser), [DERA p.Ala131Thr](/variant/dera-p-ala131thr), [DERA p.Ala228Gly](/variant/dera-p-ala228gly), [DERA p.Ala262Val](/variant/dera-p-ala262val), [DERA p.Ala29Val](/variant/dera-p-ala29val), [DERA p.Arg105Gly](/variant/dera-p-arg105gly), [DERA p.Arg105Trp](/variant/dera-p-arg105trp), [DERA p.Arg176Cys](/variant/dera-p-arg176cys).

### 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 4659636). 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.*