Is AGBL5 p.Arg705Gln (c.2114G>A) pathogenic?

AGBL5 p.Arg705Gln (c.2114G>A) is classified Uncertain significance in AGBL5 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-11-23). AlphaMissense: likely benign (0.108); Ultra-rare (popmax 0.0167%, amr); Associated with inherited retinal dystrophy.

What condition is associated with AGBL5 p.Arg705Gln (c.2114G>A)?

AGBL5 p.Arg705Gln (c.2114G>A) is associated with inherited retinal dystrophy (ClinVar).

How common is AGBL5 p.Arg705Gln (c.2114G>A) in the general population?

AGBL5 p.Arg705Gln (c.2114G>A) is ultra-rare (popmax 0.0167%, amr) (gnomAD).

What do computational predictors say about AGBL5 p.Arg705Gln (c.2114G>A)?

AlphaMissense predicts likely benign (score 0.108) — an in-silico prediction, not a clinical call.

AGBL5 p.Arg705Gln

c.2114G>A · rs768662881 · VCV1492409

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.108 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0167%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

inherited retinal dystrophy

Computational evidence

Protein change
AlphaMissense	0.108	likely benign
REVEL	0.063	moderately benign-leaning
SaProt	LLR -6.06	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 4.6	GERP 0.35, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 13 kb · p 0.75 · regional, not allelic
Overall
CADD	24.0	PHRED · no single calibrated threshold — expert panels disagree

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

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0167% Admixed American · 10/59,984 alleles

Filtering AF 0.009% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00681%

Overall 0.00161% 26/1,613,924 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0167%	5,998
Remaining individualsnot grpmax-eligible	0.0048%	20,830
Finnishnot grpmax-eligible	0.00312%	32,005
African / African-American	0.00267%	37,441
East Asian	0.00223%	44,874
South Asian	0.0011%	91,080
European (non-Finnish)	0.000593%	168,573

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.Arg705Gln
Coding: c.2114G>A
MANE Select: NM_021831
dbSNP: rs768662881
Type: single nucleotide variant
Location: chr2:27067518 (GRCh38)
Gene constraint: LOEUF 0.709 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.36 · 10 PDB
Residue 705: 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

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.Arg705Trp 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
AGBL5 p.Arg598His 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-arg705gln (accessed [today's date]).

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