Is AGBL5 p.Pro542fs (c.1622dup) pathogenic?

AGBL5 p.Pro542fs (c.1622dup) is classified Pathogenic in AGBL5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-21). Very rare (popmax 6.84e-05%).

How common is AGBL5 p.Pro542fs (c.1622dup) in the general population?

AGBL5 p.Pro542fs (c.1622dup) is very rare (popmax 6.84e-05%) (gnomAD).

AGBL5 p.Pro542fs

c.1622dup · rs1668490262 · VCV2010574

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 6.84e-05%)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 9 of 15
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 10	GERP 2.5, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 6.84e-05%

Overall 6.84e-05% 1/1,461,718 alleles · very rare

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.Pro542fs
Coding: c.1622dup
MANE Select: NM_021831
dbSNP: rs1668490262
Type: Duplication
Location: chr2:27057383 (GRCh38)
Gene constraint: LOEUF 0.709 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.36 · 10 PDB
Residue 542: 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 UniProt-annotated variant site (in rp75); an α-helix

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

Similar variants

AGBL5 c.2090-2dup Uncertain significance ★★ same type
AGBL5 c.216-14dup Likely benign ★★ same type
AGBL5 c.552-9dup Benign/Likely benign ★★ same type
AGBL5 p.Ala428fs Pathogenic ★ same type
AGBL5 p.Arg549fs Pathogenic ★ same type
AGBL5 p.Asn625fs Pathogenic ★ same type
AGBL5 p.His141fs Pathogenic ★ same type
AGBL5 p.Leu247fs Pathogenic ★ 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-pro542fs (accessed [today's date]).

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