# NM_021831.6(AGBL5):c.2374C>T (p.Arg792Trp)

https://sugi.bio/variant/agbl5-p-arg792trp

## Summary

**AGBL5 p.Arg792Trp (c.2374C>T)** is classified **Uncertain significance** in AGBL5 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-01-16). AlphaMissense: likely benign (0.112); Ultra-rare (popmax 0.0156%, eas); Associated with inherited retinal dystrophy.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs1387767975 · 2 submitters · 1 linked condition · AlphaMissense likely benign · ultra-rare (popmax 0.0156%, eas)

## For patients & families {#patients}

This is a change in the AGBL5 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters, and is linked to inherited retinal dystrophy.

*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.*

|  |  |
| --- | --- |
| Clinical trials | 40 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0018916/index) · [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.Arg792Trp |
| Coding change (HGVS c.) | c.2374C>T |
| MANE Select transcript | [NM_021831](https://www.ncbi.nlm.nih.gov/nuccore/NM_021831) |
| dbSNP | [rs1387767975](https://www.ncbi.nlm.nih.gov/snp/rs1387767975/) |
| Variant type | single nucleotide variant |
| Location | chr2:27069591-27069591 (GRCh38) |
| ClinVar | [VCV3028775](https://www.ncbi.nlm.nih.gov/clinvar/variation/3028775/) |

**All HGVS expressions:** `NC_000002.11:g.27292459C>T`, `NC_000002.12:g.27069591C>T`, `NG_052914.1:g.23169C>T`, `NM_001035506.1:c.2374C>T`, `NM_021831.5:c.2374C>T`, `NM_021831.6:c.2374C>T`, `NR_104246.2:n.2593C>T`, `NR_138023.2:n.2599C>T`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.112)
- REVEL 0.043 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -8.135 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 2.711, GERP -0.02, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 24.2**. 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 1.01** across the covering region of the MANE Select transcript (27,057,317–27,070,260), spanning 12,943 bp. Chi-square p 0.75. 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>G, Δ0.24 acceptor 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 (gnomAD v4.1): grpmax **0.0156%** (eas) · FAF95 0.00726% · FAF99 0.00515% · 7/44,878 in the highest group · 14/1,614,102 alleles overall — ultra-rare (popmax 0.0156%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.0156% | 6,411 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.00338% | 29,604 |
| African / African-American | 0.00133% | 75,042 |
| South Asian | 0.0011% | 91,084 |
| European (non-Finnish) | 0.000339% | 294,989 |

*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 **792** lies in a UniProt-annotated variant site (found in patients with a usher-like phenotype encompassing rp and hearing loss; likely pathogenic); a UniProt-annotated variant site (in rp75); the 'disordered' region.

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}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-01-16.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2023–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Dept Of Ophthalmology, Nagoya University | Uncertain significance | criteria provided, single submitter | research | 2023-10-01 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-01-16 |

## Associated conditions {#conditions}

[inherited retinal dystrophy](https://sugi.bio/atlas/disease/inherited-retinal-dystrophy/).

**Reported phenotype names (ClinVar):** Retinal dystrophy, Inborn genetic diseases, Inherited retinal dystrophy.

## Similar variants {#similar}

Related AGBL5 variant pages (same residue, condition, or type): [AGBL5 p.Arg792Gln](/variant/agbl5-p-arg792gln), [AGBL5 p.Trp592Ter](/variant/agbl5-p-trp592ter), [AGBL5 p.Arg147Cys](/variant/agbl5-p-arg147cys), [AGBL5 p.Arg341His](/variant/agbl5-p-arg341his), [AGBL5 p.Arg487Gln](/variant/agbl5-p-arg487gln), [AGBL5 p.Arg489His](/variant/agbl5-p-arg489his), [AGBL5 p.Arg537His](/variant/agbl5-p-arg537his), [AGBL5 p.Arg598His](/variant/agbl5-p-arg598his).

### 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 3028775). 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.*