Is AGBL5 p.Arg193Trp (c.577C>T) pathogenic?

AGBL5 p.Arg193Trp (c.577C>T) is classified Likely pathogenic in AGBL5 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-27). AlphaMissense: likely pathogenic (0.9845); Very rare (popmax 0.000254%, nfe); Associated with inherited retinal dystrophy.

What condition is associated with AGBL5 p.Arg193Trp (c.577C>T)?

AGBL5 p.Arg193Trp (c.577C>T) is associated with inherited retinal dystrophy (ClinVar).

How common is AGBL5 p.Arg193Trp (c.577C>T) in the general population?

AGBL5 p.Arg193Trp (c.577C>T) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about AGBL5 p.Arg193Trp (c.577C>T)?

AlphaMissense predicts likely pathogenic (score 0.9845) — an in-silico prediction, not a clinical call.

AGBL5 p.Arg193Trp

c.577C>T · VCV3381770

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9845 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

inherited retinal dystrophy

Computational evidence

Protein change
AlphaMissense	0.9845	likely pathogenic ✓ concordant with ClinVar
REVEL	0.533	indeterminate
SaProt	LLR -14.70	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.22 · evaluated, not missing
Constraint at this position
Conservation	phyloP 6.1	GERP 2.4, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 4,357 bp · p 1.1e-07 · regional, not allelic
Overall
CADD	32.0	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 0.000254% European (non-Finnish) · 3/1,179,958 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000248% 4/1,613,834 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,472
European (non-Finnish)grpmax	0.000254%	393,320

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg193Trp
Coding: c.577C>T
MANE Select: NM_021831
Type: single nucleotide variant
Location: chr2:27054655 (GRCh38)
Gene constraint: LOEUF 0.709 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.36 · 10 PDB
Residue 193: the peptidase m14 domain; a UniProt-annotated variant site (found in patients with a usher-like phenotype encompassing rp and hearing loss; likely pathogenic); a β-strand

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

Disease context

inherited retinal dystrophy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

AGBL5 p.Arg193Leu Uncertain significance ★★ ⚠ same residue
AGBL5 p.Arg193Gln Uncertain significance ★ ⚠ same residue
AGBL5 p.Trp592Ter Pathogenic ★★ same condition
AGBL5 p.Arg147Cys Uncertain significance ★★ ⚠ same condition
AGBL5 p.Arg341His Uncertain significance ★★ ⚠ same condition
AGBL5 p.Arg487Gln Uncertain significance ★★ ⚠ same condition
AGBL5 p.Arg489His Uncertain significance ★★ ⚠ same condition
AGBL5 p.Arg537His 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-arg193trp (accessed [today's date]).

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