# NM_001330701.2(AGTPBP1):c.2733T>C (p.Pro911=)

https://sugi.bio/variant/agtpbp1-p-pro911

## Summary

**AGTPBP1 p.Pro911= (c.2733T>C)** is classified **Likely benign** in AGTPBP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-03). Ultra-rare (popmax 0.0558%, eas); Associated with Inborn genetic diseases.

**At a glance:** Likely benign · review: Single submitter · 1 submitter · 1 linked condition · ultra-rare (popmax 0.0558%, eas)

## For patients & families {#patients}

This is a change in the AGTPBP1 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to Inborn genetic diseases.

*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 | [AGTPBP1](https://sugi.bio/atlas/gene/AGTPBP1/) |
| Protein change (HGVS p.) | p.Pro911= |
| Coding change (HGVS c.) | c.2733T>C |
| MANE Select transcript | [NM_001330701](https://www.ncbi.nlm.nih.gov/nuccore/NM_001330701) |
| Variant type | single nucleotide variant |
| Location | chr9:85588468-85588468 (GRCh38) |
| ClinVar | [VCV4572895](https://www.ncbi.nlm.nih.gov/clinvar/variation/4572895/) |

**All HGVS expressions:** `NC_000009.11:g.88203383A>G`, `NC_000009.12:g.85588468A>G`, `NM_001286715.1:c.2889T>C`, `NM_001286717.1:c.2769T>C`, `NM_001330701.2:c.2733T>C`, `NM_015239.3:c.2613T>C`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor gain** (Δ 0.21) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 0.213, GERP 0.752, phastCons 0.289 — weakly conserved position
- CADD: **PHRED 7.15**. 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 deltas (raw): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.21**, donor gain **0.00**. Largest is acceptor gain, 10 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Population frequency (gnomAD v4.1): grpmax **0.0558%** (eas) · FAF95 0.0387% · FAF99 0.0331% · 25/44,798 in the highest group · 27/1,610,972 alleles overall — ultra-rare (popmax 0.0558%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.0558% | 1,792 |
| Remaining individuals (not grpmax-eligible) | 0.00321% | 31,187 |

*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}

**AGTPBP1** population constraint: LOEUF 0.556, pLI 0.0066485, missense-Z 2.5632. *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):

- **neurodegeneration, childhood-onset, with cerebellar atrophy** — Definitive (AR)

## Protein context {#protein}

Residue **911** lies in the peptidase m14 domain; a UniProt-annotated variant site (in condca); a UniProt-annotated variant site (in condca; loss of tubulin deglutamylation; patient cells show lack of protein and excess of tubulin polyglutamylation).

AlphaFold model confidence (whole protein): pLDDT 75.95, 54% of residues very-high.

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

*Describes the biological roles of AGTPBP1 (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:** AGTPBP1's established molecular role includes metallocarboxypeptidase activity. p.Pro911= falls in the peptidase m14 domain.


### Pathways affected {#pathways}

AGTPBP1 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Carboxyterminal post-translational modifications of tubulin](https://reactome.org/content/detail/R-HSA-8955332) | electronic |

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

**Molecular function:** metallocarboxypeptidase activity.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-11-03.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2025-11-03 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases.

## Similar variants {#similar}

Related AGTPBP1 variant pages (same residue, condition, or type): [AGTPBP1 p.Ala461Gly](/variant/agtpbp1-p-ala461gly), [AGTPBP1 p.Arg1136His](/variant/agtpbp1-p-arg1136his), [AGTPBP1 p.Glu1176Gly](/variant/agtpbp1-p-glu1176gly), [AGTPBP1 p.Ala1065Thr](/variant/agtpbp1-p-ala1065thr), [AGTPBP1 p.Ala140Thr](/variant/agtpbp1-p-ala140thr), [AGTPBP1 p.Arg1008His](/variant/agtpbp1-p-arg1008his), [AGTPBP1 p.Arg100Gln](/variant/agtpbp1-p-arg100gln), [AGTPBP1 p.Arg1086Cys](/variant/agtpbp1-p-arg1086cys).

### 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 4572895). 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.*