# NM_000502.6(EPX):c.451C>T (p.Arg151Trp)

https://sugi.bio/variant/epx-p-arg151trp

## Summary

**EPX p.Arg151Trp (c.451C>T)** is classified **Uncertain significance** in EPX (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-11). AlphaMissense: likely benign (0.1257); Rare (popmax 0.135%, sas).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs370404238 · 1 submitter · AlphaMissense likely benign · rare (popmax 0.135%, sas)

## For patients & families {#patients}

This is a change in the EPX 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 | [EPX](https://sugi.bio/atlas/gene/EPX/) |
| Protein change (HGVS p.) | p.Arg151Trp |
| Coding change (HGVS c.) | c.451C>T |
| MANE Select transcript | [NM_000502](https://www.ncbi.nlm.nih.gov/nuccore/NM_000502) |
| dbSNP | [rs370404238](https://www.ncbi.nlm.nih.gov/snp/rs370404238/) |
| Variant type | single nucleotide variant |
| Location | chr17:58193818-58193818 (GRCh38) |
| ClinVar | [VCV2205099](https://www.ncbi.nlm.nih.gov/clinvar/variation/2205099/) |

**All HGVS expressions:** `NC_000017.10:g.56271179C>T`, `NC_000017.11:g.58193818C>T`, `NG_013020.1:g.6091C>T`, `NM_000502.6:c.451C>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** (0.1257)
- REVEL 0.232 (benign-leaning) — agrees with AlphaMissense
- SaProt LLR -7.991 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP -0.776, GERP -4.03 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 20.2**. 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 (58,192,847–58,204,420), spanning 11,573 bp. Chi-square p 0.44. 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, Δ0.83 donor gain), 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 **0.135%** (sas) · FAF95 0.116% · FAF99 0.108% · 123/91,018 in the highest group · 174/1,611,150 alleles overall — rare (popmax 0.135%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.135% | 740 |
| Middle Eastern | 0.0337% | 2,967 |
| African / African-American | 0.008% | 12,501 |
| Admixed American | 0.005% | 20,008 |
| European (non-Finnish) | 0.00323% | 30,985 |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,206 |

*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}

**EPX** population constraint: LOEUF 0.984, pLI 3.3395e-15, missense-Z 0.73859. *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 **151** lies in a disulfide bond.

AlphaFold model confidence (whole protein): pLDDT 92.40, 82% of residues very-high.

**1 experimental structure(s)** (PDB): [8OGI](https://www.rcsb.org/structure/8OGI).

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

*Describes the biological roles of EPX (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.*


### Pathways affected {#pathways}

EPX participates in **1 Reactome pathway** (⚕ = disease pathway):

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

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-08-11.

**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 | 2025-08-11 |

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

## Similar variants {#similar}

Related EPX variant pages (same residue, condition, or type): [EPX p.Arg151Gln](/variant/epx-p-arg151gln), [EPX c.170+5A>G](/variant/epx-c-170-plus-5a-g), [EPX c.464+8C>T](/variant/epx-c-464-plus-8c-t), [EPX c.801+1G>A](/variant/epx-c-801-plus-1g-a), [EPX p.Asn572Tyr](/variant/epx-p-asn572tyr), [EPX p.Cys257Ter](/variant/epx-p-cys257ter), [EPX p.Leu624=](/variant/epx-p-leu624), [EPX p.Phe308Leu](/variant/epx-p-phe308leu).

### 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 2205099). 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.*