# NM_003294.4(TPSAB1):c.308C>G (p.Pro103Arg)

https://sugi.bio/variant/tpsab1-p-pro103arg

## Summary

**TPSAB1 p.Pro103Arg (c.308C>G)** is classified **Uncertain significance** in TPSAB1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-30). AlphaMissense: likely benign (0.139); Very rare (popmax 0.00243%, sas).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.00243%, sas)

## For patients & families {#patients}

This is a change in the TPSAB1 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 | [TPSAB1](https://sugi.bio/atlas/gene/TPSAB1/) |
| Protein change (HGVS p.) | p.Pro103Arg |
| Coding change (HGVS c.) | c.308C>G |
| MANE Select transcript | [NM_003294](https://www.ncbi.nlm.nih.gov/nuccore/NM_003294) |
| Variant type | single nucleotide variant |
| Location | chr16:1241508-1241508 (GRCh38) |
| ClinVar | [VCV3460587](https://www.ncbi.nlm.nih.gov/clinvar/variation/3460587/) |

**All HGVS expressions:** `NC_000016.10:g.1241508C>G`, `NC_000016.9:g.1291509C>G`, `NM_003294.4:c.308C>G`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.139)
- REVEL 0.438 (indeterminate)
- Conservation: phyloP -20, GERP -3.35 — fast-evolving / accelerated position
- **SaProt:** withheld — SaProt scored this protein on a different isoform than AlphaMissense numbered the variant on, and the two diverge from residue 51, so a score under this position number would describe a different residue.
- CADD: **PHRED 4.245**. 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 0.10** across the covering region of the MANE Select transcript (1,241,319–1,241,693), spanning 374 bp — the region is depleted of missense variation. Chi-square p 2.3e-20. 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, Δ0.24 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 **0.00243%** (sas) · FAF95 0.000404% · FAF99 0.000151% · 2/82,142 in the highest group · 3/1,516,508 alleles overall — very rare (popmax 0.00243%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.00243% | 41,071 |
| European (non-Finnish) | 8.88e-05% | 1,126,012 |

*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}

**TPSAB1** population constraint: LOEUF 1.9, pLI 2.4474e-06, missense-Z -0.3743; ClinGen dosage — haploinsufficiency 0/3, triplosensitivity 3/3. *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 **103** lies in the peptidase s1 domain.

AlphaFold model confidence (whole protein): pLDDT 91.80, 86% of residues very-high.

**22 experimental structure(s)** (PDB): [1LTO](https://www.rcsb.org/structure/1LTO), [2F9N](https://www.rcsb.org/structure/2F9N), [2F9O](https://www.rcsb.org/structure/2F9O), [2F9P](https://www.rcsb.org/structure/2F9P), [2ZEB](https://www.rcsb.org/structure/2ZEB), [2ZEC](https://www.rcsb.org/structure/2ZEC) — incl. mutant structure 2F9N.

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

*Describes the biological roles of TPSAB1 (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:** TPSAB1's established molecular role includes identical protein binding. p.Pro103Arg falls in the peptidase s1 domain.


### Pathways affected {#pathways}

TPSAB1 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Activation of Matrix Metalloproteinases](https://reactome.org/content/detail/R-HSA-1592389) | curated |

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

**Molecular function:** identical protein binding.

**Biological process:** extracellular matrix disassembly.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-07-30.

**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 | 2024-07-30 |

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

## Similar variants {#similar}

Related TPSAB1 variant pages (same residue, condition, or type): [TPSAB1 p.Pro103Leu](/variant/tpsab1-p-pro103leu), [TPSAB1 p.Pro103=](/variant/tpsab1-p-pro103), [TPSAB1 p.Val76Met](/variant/tpsab1-p-val76met), [TPSAB1 c.1-105C>A](/variant/tpsab1-c-1-minus-105c-a), [TPSAB1 c.233+12G>A](/variant/tpsab1-c-233-plus-12g-a), [TPSAB1 c.233+30G>C](/variant/tpsab1-c-233-plus-30g-c), [TPSAB1 c.61+75T>C](/variant/tpsab1-c-61-plus-75t-c), [TPSAB1 c.62-27C>T](/variant/tpsab1-c-62-minus-27c-t).

### 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 3460587). 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.*