# NM_021831.6(AGBL5):c.474C>G (p.Pro158=)

https://sugi.bio/variant/agbl5-p-pro158

## Summary

**AGBL5 p.Pro158= (c.474C>G)** is classified **Likely benign** in AGBL5 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-19). Absent from gnomAD v4.1.

**At a glance:** Likely benign · review: Single submitter · rsID rs780508825 · 1 submitter · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the AGBL5 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 | [AGBL5](https://sugi.bio/atlas/gene/AGBL5/) |
| Protein change (HGVS p.) | p.Pro158= |
| Coding change (HGVS c.) | c.474C>G |
| MANE Select transcript | [NM_021831](https://www.ncbi.nlm.nih.gov/nuccore/NM_021831) |
| dbSNP | [rs780508825](https://www.ncbi.nlm.nih.gov/snp/rs780508825/) |
| Variant type | single nucleotide variant |
| Location | chr2:27053982-27053982 (GRCh38) |
| ClinVar | [VCV2024777](https://www.ncbi.nlm.nih.gov/clinvar/variation/2024777/) |

**All HGVS expressions:** `NC_000002.11:g.27276850C>G`, `NC_000002.12:g.27053982C>G`, `NG_052914.1:g.7560C>G`, `NM_001035506.1:c.474C>G`, `NM_001035507.3:c.474C>G`, `NM_021831.6:c.474C>G`, `NR_104246.2:n.646C>G`, `NR_138023.2:n.652C>G`

## 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 0.73, GERP -2.27, phastCons 0.999 — weakly conserved position
- CADD: **PHRED 14.45**. 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>T, Δ0.20 acceptor 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: **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}

**AGBL5** population constraint: LOEUF 0.709, pLI 1.6548e-08, missense-Z 1.9344. *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):

- **inherited retinal dystrophy** — Definitive (AR)

## Protein context {#protein}

Residue **158** lies in the peptidase m14 domain; a UniProt-annotated variant site (found in patients with a usher-like phenotype encompassing rp and hearing loss; likely pathogenic).

AlphaFold model confidence (whole protein): pLDDT 71.36, 54% of residues very-high.

**10 experimental structure(s)** (PDB): [8V3M](https://www.rcsb.org/structure/8V3M), [8V3N](https://www.rcsb.org/structure/8V3N), [8V3O](https://www.rcsb.org/structure/8V3O), [8V3P](https://www.rcsb.org/structure/8V3P), [8V3Q](https://www.rcsb.org/structure/8V3Q), [8V3R](https://www.rcsb.org/structure/8V3R).

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

*Describes the biological roles of AGBL5 (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.*


### Pathways affected {#pathways}

AGBL5 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 |

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-08-19.

**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 | 2022-08-19 |

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

## Similar variants {#similar}

Related AGBL5 variant pages (same residue, condition, or type): [AGBL5 p.Arg220Ter](/variant/agbl5-p-arg220ter), [AGBL5 p.Arg487Ter](/variant/agbl5-p-arg487ter), [AGBL5 p.Trp592Ter](/variant/agbl5-p-trp592ter), [AGBL5 p.Tyr485Ter](/variant/agbl5-p-tyr485ter), [AGBL5 c.2355+4A>G](/variant/agbl5-c-2355-plus-4a-g), [AGBL5 c.551+5C>A](/variant/agbl5-c-551-plus-5c-a), [AGBL5 p.Ala530Thr](/variant/agbl5-p-ala530thr), [AGBL5 p.Ala570Val](/variant/agbl5-p-ala570val).

### 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 2024777). 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.*