Is AGBL5 p.Val321Ile (c.961G>A) pathogenic?

AGBL5 p.Val321Ile (c.961G>A) is classified Conflicting classifications of pathogenicity in AGBL5 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2023-10-01). AlphaMissense: likely benign (0.0646); Ultra-rare (popmax 0.0593%, sas); Associated with inherited retinal dystrophy.

What condition is associated with AGBL5 p.Val321Ile (c.961G>A)?

AGBL5 p.Val321Ile (c.961G>A) is associated with inherited retinal dystrophy (ClinVar).

How common is AGBL5 p.Val321Ile (c.961G>A) in the general population?

AGBL5 p.Val321Ile (c.961G>A) is ultra-rare (popmax 0.0593%, sas) (gnomAD).

What do computational predictors say about AGBL5 p.Val321Ile (c.961G>A)?

AlphaMissense predicts likely benign (score 0.0646) — an in-silico prediction, not a clinical call.

AGBL5 p.Val321Ile

c.961G>A · rs755544280 · VCV1520402

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0646 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0593%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

inherited retinal dystrophy

Computational evidence

Protein change
AlphaMissense	0.0646	likely benign
REVEL	0.073	moderately benign-leaning
SaProt	LLR -7.97	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.021	GERP -5
Regional constraint	o/e 0.80	unconstrained · MANE · 4,357 bp · p 1.1e-07 · regional, not allelic
Overall
CADD	10.17	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 0.0593% South Asian · 54/91,088 alleles

Filtering AF 0.0466% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0421%

Overall 0.00434% 70/1,613,968 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0593%	1,687
Remaining individualsnot grpmax-eligible	0.0064%	15,623
East Asian	0.00446%	22,440
Admixed American	0.00333%	30,001
African / African-American	0.00267%	37,453
Finnishnot grpmax-eligible	0.00156%	63,968
European (non-Finnish)	0.000424%	236,007

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.Val321Ile
Coding: c.961G>A
MANE Select: NM_021831
dbSNP: rs755544280
Type: single nucleotide variant
Location: chr2:27055734 (GRCh38)
Gene constraint: LOEUF 0.709 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.36 · 10 PDB
Residue 321: 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 turn

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.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
AGBL5 p.Arg598His Uncertain significance ★★ ⚠ same condition
AGBL5 p.Arg673Trp 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-val321ile (accessed [today's date]).

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