# NM_005656.4(TMPRSS2):c.1467G>A (p.Arg489=)

https://sugi.bio/variant/tmprss2-p-arg489

## Summary

**TMPRSS2 p.Arg489= (c.1467G>A)** is classified **Likely benign** in TMPRSS2 (ClinVar, Single submitter, 3 submitters; last evaluated 2025-04-01). Rare (popmax 0.648%, nfe).

**At a glance:** Likely benign · review: Single submitter · rsID rs142750000 · 3 submitters · rare (popmax 0.648%, nfe)

## For patients & families {#patients}

This is a change in the TMPRSS2 gene that is classified as likely benign — not considered disease-causing, submitted by 3 submitters.

*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 | [TMPRSS2](https://sugi.bio/atlas/gene/TMPRSS2/) |
| Protein change (HGVS p.) | p.Arg489= |
| Coding change (HGVS c.) | c.1467G>A |
| MANE Select transcript | [NM_005656](https://www.ncbi.nlm.nih.gov/nuccore/NM_005656) |
| dbSNP | [rs142750000](https://www.ncbi.nlm.nih.gov/snp/rs142750000/) |
| Variant type | single nucleotide variant |
| Location | chr21:41467734-41467734 (GRCh38) |
| ClinVar | [VCV425275](https://www.ncbi.nlm.nih.gov/clinvar/variation/425275/) |

**All HGVS expressions:** `LRG_1368:g.68383G>A`, `LRG_1368t1:c.1467G>A`, `NC_000021.8:g.42839661C>T`, `NC_000021.9:g.41467734C>T`, `NG_047085.2:g.68383G>A`, `NM_001135099.1:c.1578G>A`, `NM_005656.4:c.1467G>A`

## 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 7.342, GERP 1.56, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 20.8**. 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: **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.
- Pangolin: Δ**0.58** (loss), gain 0.01 / loss 0.58. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.648%** (nfe) · FAF95 0.635% · FAF99 0.63% · 7,642/1,179,940 in the highest group · 8,096/1,614,000 alleles overall — rare (popmax 0.648%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.648% | 154 |
| Remaining individuals (not grpmax-eligible) | 0.37% | 271 |
| African / African-American | 0.121% | 824 |
| Admixed American | 0.115% | 870 |
| South Asian | 0.0417% | 2,396 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.0304% | 3,288 |
| Finnish (not grpmax-eligible) | 0.0234% | 4,269 |
| Middle Eastern | 0.0165% | 6,062 |

*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}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-04-01.

**Submitter consensus:** unanimous (2/2 Likely benign).

**Submission history:** 20 submissions (2022–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2022-04-22 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2025-04-01 |
| Dr. Peter K. Rogan Lab, Western University |  | no classification provided | in vitro |  |

**Reported phenotype names (ClinVar):** not provided, TMPRSS2-related disorder, Uterine corpus endometrial carcinoma, Nonpapillary renal cell carcinoma, Cervical cancer, Colon adenocarcinoma, Gastric cancer, Thyroid cancer, nonmedullary, 1, Malignant tumor of esophagus, Lung cancer.

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 2026-10-14); 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 425275). 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.*