Is AGBL5 p.Pro417fs (c.1250_1251del) pathogenic?

AGBL5 p.Pro417fs (c.12501251del) is classified Pathogenic in AGBL5 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-05). Very rare (popmax 0.00167%, amr).

How common is AGBL5 p.Pro417fs (c.1250_1251del) in the general population?

AGBL5 p.Pro417fs (c.1250_1251del) is very rare (popmax 0.00167%, amr) (gnomAD).

AGBL5 p.Pro417fs

c.1250_1251del · rs1433176317 · VCV1070126

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

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 7 of 15
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 2.8	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 0.00167% Admixed American · 1/60,026 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000684% 10/1,461,886 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,026
Remaining individualsnot grpmax-eligible	0.0016%	62,508
European (non-Finnish)	0.000678%	147,505

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.Pro417fs
Coding: c.1250_1251del
MANE Select: NM_021831
dbSNP: rs1433176317
Type: Deletion
Location: chr2:27056023 (GRCh38)
Gene constraint: LOEUF 0.709 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.36 · 10 PDB
Residue 417: the peptidase m14 domain; a UniProt-annotated variant site (found in patients with a usher-like phenotype encompassing rp and hearing loss; likely pathogenic)

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

Similar variants

AGBL5 p.Pro417= Likely benign ★ same residue
AGBL5 p.Ser737del Uncertain significance ★★ same type
AGBL5 c.2090-18_2090-16del Benign/Likely benign ★★ same type
AGBL5 c.2090-7del Likely benign ★★ same type
AGBL5 c.552-9del Benign/Likely benign ★★ same type
AGBL5 c.1874+2_1874+5del Likely pathogenic ★ same type
AGBL5 p.Gln372fs Likely pathogenic ★ same type
AGBL5 p.Gln708fs Likely 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-pro417fs (accessed [today's date]).

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