# NM_022350.5(ERAP2):c.1469C>A (p.Ala490Asp)

https://sugi.bio/variant/erap2-p-ala490asp

## Summary

**ERAP2 p.Ala490Asp (c.1469C>A)** is classified **Uncertain significance** in ERAP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-24). AlphaMissense: likely pathogenic (0.8456); Ultra-rare (popmax 0.0259%, eas).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs376575375 · 1 submitter · AlphaMissense likely pathogenic · ultra-rare (popmax 0.0259%, eas)

## For patients & families {#patients}

This is a change in the ERAP2 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 | [ERAP2](https://sugi.bio/atlas/gene/ERAP2/) |
| Protein change (HGVS p.) | p.Ala490Asp |
| Coding change (HGVS c.) | c.1469C>A |
| MANE Select transcript | [NM_001040458](https://www.ncbi.nlm.nih.gov/nuccore/NM_001040458) (variant reported on NM_022350) |
| dbSNP | [rs376575375](https://www.ncbi.nlm.nih.gov/snp/rs376575375/) |
| Variant type | single nucleotide variant |
| Location | chr5:96896829-96896829 (GRCh38) |
| ClinVar | [VCV2341351](https://www.ncbi.nlm.nih.gov/clinvar/variation/2341351/) |

**All HGVS expressions:** `NC_000005.10:g.96896829C>A`, `NC_000005.9:g.96232533C>A`, `NG_027839.2:g.44155G>T`, `NG_051092.1:g.25891C>A`, `NM_001130140.3:c.1469C>A`, `NM_001329229.2:c.1334C>A`, `NM_022350.5:c.1469C>A`, `NR_137637.2:n.2135C>A`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.8456)
- REVEL 0.263 (benign-leaning) — differs from AlphaMissense
- SaProt LLR -14.067 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt call this damaging; REVEL does not
- Conservation: phyloP 1.712, GERP 2.25, phastCons 0.02 — weakly conserved position
- CADD: **PHRED 24.3**. 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 0.99** across the covering region of the MANE Select transcript (96,879,686–96,909,582), spanning 29,896 bp. Chi-square p 0.75. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not looked up on this page** — it was served without the gene's SpliceAI index, so no lookup was made. This is a gap in this page, not in the data, and says nothing about whether a splicing effect is predicted.
- Population frequency (gnomAD v4.1): grpmax **0.0259%** (eas) · FAF95 0.0113% · FAF99 0.00767% · 6/23,134 in the highest group · 27/1,227,472 alleles overall — ultra-rare (popmax 0.0259%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.0259% | 3,856 |
| Remaining individuals (not grpmax-eligible) | 0.0022% | 45,382 |
| European (non-Finnish) | 0.00208% | 48,019 |

*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.*

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-04-24.

**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 | 2024-04-24 |

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

### 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 2341351). 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.*