# NM_001979.6(EPHX2):c.1061C>T (p.Ala354Val)

https://sugi.bio/variant/ephx2-p-ala354val

## Summary

**EPHX2 p.Ala354Val (c.1061C>T)** is classified **Uncertain significance** in EPHX2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-01). AlphaMissense: likely pathogenic (0.5972); Very rare (popmax 0.0022%, sas).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs76549048 · 1 submitter · AlphaMissense likely pathogenic · very rare (popmax 0.0022%, sas)

## For patients & families {#patients}

This is a change in the EPHX2 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 | [EPHX2](https://sugi.bio/atlas/gene/EPHX2/) |
| Protein change (HGVS p.) | p.Ala354Val |
| Coding change (HGVS c.) | c.1061C>T |
| MANE Select transcript | [NM_001979](https://www.ncbi.nlm.nih.gov/nuccore/NM_001979) |
| dbSNP | [rs76549048](https://www.ncbi.nlm.nih.gov/snp/rs76549048/) |
| Variant type | single nucleotide variant |
| Location | chr8:27525364-27525364 (GRCh38) |
| ClinVar | [VCV2227176](https://www.ncbi.nlm.nih.gov/clinvar/variation/2227176/) |

**All HGVS expressions:** `NC_000008.10:g.27382881C>T`, `NC_000008.11:g.27525364C>T`, `NG_012064.1:g.39237C>T`, `NM_001256482.2:c.902C>T`, `NM_001256483.2:c.863C>T`, `NM_001256484.2:c.902C>T`, `NM_001979.6:c.1061C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.5972)
- REVEL 0.654 (pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -13.47 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 7.503, GERP 1.58, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 27.6**. 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 1.02** across the covering region of the MANE Select transcript (27,491,209–27,544,519), spanning 53,310 bp. Chi-square p 0.64. 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, Δ0.40 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 **0.0022%** (sas) · FAF95 0.000615% · FAF99 0.000474% · 2/91,072 in the highest group · 19/1,613,756 alleles overall — very rare (popmax 0.0022%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,243 |
| South Asian (grpmax) | 0.0022% | 45,536 |
| Admixed American | 0.00167% | 59,994 |
| Finnish (not grpmax-eligible) | 0.00156% | 64,028 |
| European (non-Finnish) | 0.0011% | 90,756 |

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}

**EPHX2** population constraint: LOEUF 1.093, pLI 4.8926e-22, missense-Z 0.023314. *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 **354** lies in the ab hydrolase-1 domain; the 'epoxide hydrolase' region; a β-strand.

AlphaFold model confidence (whole protein): pLDDT 93.54, 81% of residues very-high.

**141 experimental structure(s)** (PDB): [1S8O](https://www.rcsb.org/structure/1S8O), [1VJ5](https://www.rcsb.org/structure/1VJ5), [1ZD2](https://www.rcsb.org/structure/1ZD2), [1ZD3](https://www.rcsb.org/structure/1ZD3), [1ZD4](https://www.rcsb.org/structure/1ZD4), [1ZD5](https://www.rcsb.org/structure/1ZD5).

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

*Describes the biological roles of EPHX2 (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:** EPHX2's established molecular role includes magnesium ion binding. p.Ala354Val falls in the ab hydrolase-1 domain.


### Pathways affected {#pathways}

EPHX2 participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Biosynthesis of maresins](https://reactome.org/content/detail/R-HSA-9018682) | other |
| [Peroxisomal protein import](https://reactome.org/content/detail/R-HSA-9033241) | other |
| [Synthesis of epoxy (EET) and dihydroxyeicosatrienoic acids (DHET)](https://reactome.org/content/detail/R-HSA-2142670) | other |

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

**Molecular function:** magnesium ion binding, epoxide hydrolase activity, toxic substance binding, phosphatase activity, lipid phosphatase activity, protein homodimerization activity.

**Biological process:** positive regulation of gene expression, dephosphorylation, cholesterol homeostasis, stilbene catabolic process, phospholipid dephosphorylation, regulation of cholesterol metabolic process.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-08-01.

**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 | 2022-08-01 |

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

## Similar variants {#similar}

Related EPHX2 variant pages (same residue, condition, or type): [EPHX2 p.Arg403Trp](/variant/ephx2-p-arg403trp), [EPHX2 p.Arg52Gln](/variant/ephx2-p-arg52gln), [EPHX2 p.Gly21=](/variant/ephx2-p-gly21), [EPHX2 p.Ala175Asp](/variant/ephx2-p-ala175asp), [EPHX2 p.Ala18Val](/variant/ephx2-p-ala18val), [EPHX2 p.Ala260Ser](/variant/ephx2-p-ala260ser), [EPHX2 p.Ala425Val](/variant/ephx2-p-ala425val), [EPHX2 p.Ala493Val](/variant/ephx2-p-ala493val).

### 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 2227176). 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.*