Is AGBL5 p.Pro628Leu (c.1883C>T) pathogenic?

AGBL5 p.Pro628Leu (c.1883C>T) is classified Conflicting classifications of pathogenicity in AGBL5 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-05-07). AlphaMissense: likely benign (0.1019); Ultra-rare (popmax 0.0958%, eas).

How common is AGBL5 p.Pro628Leu (c.1883C>T) in the general population?

AGBL5 p.Pro628Leu (c.1883C>T) is ultra-rare (popmax 0.0958%, eas) (gnomAD).

What do computational predictors say about AGBL5 p.Pro628Leu (c.1883C>T)?

AlphaMissense predicts likely benign (score 0.1019) — an in-silico prediction, not a clinical call.

AGBL5 p.Pro628Leu

c.1883C>T · rs188976918 · VCV1673328

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1019 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0958%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1019	likely benign
REVEL	0.158	moderately benign-leaning
SaProt	LLR -6.98	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 4.9	GERP 1.3, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 13 kb · p 0.75 · regional, not allelic
Overall
CADD	25.7	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 0.0958% East Asian · 43/44,884 alleles

Filtering AF 0.0731% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.065%

Overall 0.00279% 45/1,613,240 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0958%	1,044
South Asian	0.0011%	91,036
European (non-Finnish)	8.48e-05%	1,179,578

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.Pro628Leu
Coding: c.1883C>T
MANE Select: NM_021831
dbSNP: rs188976918
Type: single nucleotide variant
Location: chr2:27059198 (GRCh38)
Gene constraint: LOEUF 0.709 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.36 · 10 PDB
Residue 628: 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

Similar variants

AGBL5 p.Pro628= Likely benign ★★ same residue
AGBL5 p.Arg220Ter Pathogenic ★★ same type
AGBL5 p.Arg487Ter Pathogenic ★★ same type
AGBL5 p.Trp592Ter Pathogenic ★★ same type
AGBL5 p.Tyr485Ter Pathogenic/Likely pathogenic ★★ same type
AGBL5 c.2355+4A>G Uncertain significance ★★ same type
AGBL5 c.551+5C>A Uncertain significance ★★ same type
AGBL5 p.Ala530Thr Uncertain significance ★★ ⚠ same type

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-pro628leu (accessed [today's date]).

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