Is AGBL5 p.Arg598Cys (c.1792C>T) pathogenic?

AGBL5 p.Arg598Cys (c.1792C>T) is classified Uncertain significance in AGBL5 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-03-25). AlphaMissense: ambiguous (0.5581); Ultra-rare (popmax 0.09%, amr); Associated with Inborn genetic diseases.

What condition is associated with AGBL5 p.Arg598Cys (c.1792C>T)?

AGBL5 p.Arg598Cys (c.1792C>T) is associated with Inborn genetic diseases (ClinVar).

How common is AGBL5 p.Arg598Cys (c.1792C>T) in the general population?

AGBL5 p.Arg598Cys (c.1792C>T) is ultra-rare (popmax 0.09%, amr) (gnomAD).

What do computational predictors say about AGBL5 p.Arg598Cys (c.1792C>T)?

AlphaMissense predicts ambiguous (score 0.5581) — an in-silico prediction, not a clinical call.

AGBL5 p.Arg598Cys

c.1792C>T · rs148469619 · VCV855243

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.5581 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.09%, amr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5581	ambiguous
REVEL	0.389	indeterminate
SaProt	LLR -10.80	damaging
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.40 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.7	GERP 2.4, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 13 kb · p 0.75 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.09% Admixed American · 54/59,996 alleles

Filtering AF 0.0708% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0639%

Overall 0.00384% 62/1,614,048 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.09%	1,111
East Asian	0.00668%	14,965
Remaining individualsnot grpmax-eligible	0.0016%	62,482
African / African-American	0.00133%	74,918
South Asian	0.0011%	91,084
European (non-Finnish)	0.000169%	590,023

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: AGBL5
Protein: p.Arg598Cys
Coding: c.1792C>T
MANE Select: NM_021831
dbSNP: rs148469619
Type: single nucleotide variant
Location: chr2:27058520 (GRCh38)
Gene constraint: LOEUF 0.709 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.36 · 10 PDB
Residue 598: 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); an α-helix

Full AGBL5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

AGBL5 p.Arg598His Uncertain significance ★★ ⚠ same residue
AGBL5 p.Ala530Thr Uncertain significance ★★ ⚠ same condition
AGBL5 p.Arg111Cys Uncertain significance ★★ ⚠ same condition
AGBL5 p.Arg121His Uncertain significance ★★ ⚠ same condition
AGBL5 p.Arg147Cys Uncertain significance ★★ ⚠ same condition
AGBL5 p.Arg147Gly Uncertain significance ★★ ⚠ same condition
AGBL5 p.Arg147His Uncertain significance ★★ ⚠ same condition
AGBL5 p.Arg174His Uncertain significance ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/agbl5-p-arg598cys (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown