# NM_182915.3(STEAP3):c.444C>A (p.Pro148=)

https://sugi.bio/variant/steap3-p-pro148

## Summary

**STEAP3 p.Pro148= (c.444C>A)** is classified **Likely benign** in STEAP3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-15). Absent from gnomAD v4.1.

**At a glance:** Likely benign · review: Single submitter · 1 submitter · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the STEAP3 gene that is classified as likely benign — not considered disease-causing, 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 | [STEAP3](https://sugi.bio/atlas/gene/STEAP3/) |
| Protein change (HGVS p.) | p.Pro148= |
| Coding change (HGVS c.) | c.444C>A |
| MANE Select transcript | [NM_182915](https://www.ncbi.nlm.nih.gov/nuccore/NM_182915) |
| Variant type | single nucleotide variant |
| Location | chr2:119245910-119245910 (GRCh38) |
| ClinVar | [VCV4780095](https://www.ncbi.nlm.nih.gov/clinvar/variation/4780095/) |

**All HGVS expressions:** `NC_000002.11:g.120003486C>A`, `NC_000002.12:g.119245910C>A`, `NG_042823.1:g.27103C>A`, `NM_001008410.2:c.414C>A`, `NM_018234.3:c.414C>A`, `NM_138637.3:c.414C>A`, `NM_182915.3:c.444C>A`, `NR_046721.1:n.1730G>T`

## Computational & population evidence {#evidence}

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

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP -1.697, GERP -3.87 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 12.18**. 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.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (C>G, Δ0.26 donor 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: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}

**STEAP3** population constraint: LOEUF 1.27, pLI 3.6907e-13, missense-Z 0.23469. *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):

- **severe congenital hypochromic anemia with ringed sideroblasts** — Disputed (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 89.24, 81% of residues very-high.

**2 experimental structure(s)** (PDB): [2VNS](https://www.rcsb.org/structure/2VNS), [2VQ3](https://www.rcsb.org/structure/2VQ3).

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

*Describes the biological roles of STEAP3 (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:** STEAP3's established molecular role includes heme binding.


### Pathways affected {#pathways}

STEAP3 participates in **7 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [CDC42 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013148) | curated |
| [RHOD GTPase cycle](https://reactome.org/content/detail/R-HSA-9013405) | curated |
| [RHOF GTPase cycle](https://reactome.org/content/detail/R-HSA-9035034) | curated |
| [RHOJ GTPase cycle](https://reactome.org/content/detail/R-HSA-9013409) | curated |
| [RHOQ GTPase cycle](https://reactome.org/content/detail/R-HSA-9013406) | curated |
| [TP53 Regulates Transcription of Genes Involved in Cytochrome C Release](https://reactome.org/content/detail/R-HSA-6803204) | curated |
| [Transferrin endocytosis and recycling](https://reactome.org/content/detail/R-HSA-917977) | curated |

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

**Molecular function:** heme binding, identical protein binding, ferric-chelate reductase (NADPH) activity, FAD binding.

**Biological process:** protein secretion.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-12-15.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-12-15 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related STEAP3 variant pages (same residue, condition, or type): [STEAP3 p.Ala490Thr](/variant/steap3-p-ala490thr), [STEAP3 p.Arg217Ser](/variant/steap3-p-arg217ser), [STEAP3 p.Arg293Trp](/variant/steap3-p-arg293trp), [STEAP3 p.Arg336His](/variant/steap3-p-arg336his), [STEAP3 p.Arg466Cys](/variant/steap3-p-arg466cys), [STEAP3 p.Gln87Arg](/variant/steap3-p-gln87arg), [STEAP3 p.Glu141Lys](/variant/steap3-p-glu141lys), [STEAP3 p.Gly379Cys](/variant/steap3-p-gly379cys).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 4780095). 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.*