Is AGBL5 p.Pro422Ser (c.1264C>T) pathogenic?

AGBL5 p.Pro422Ser (c.1264C>T) is classified Uncertain significance in AGBL5 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-01-15). AlphaMissense: likely benign (0.2712); Very rare (popmax 0.01%, amr); Associated with Inborn genetic diseases.

What condition is associated with AGBL5 p.Pro422Ser (c.1264C>T)?

AGBL5 p.Pro422Ser (c.1264C>T) is associated with Inborn genetic diseases (ClinVar).

How common is AGBL5 p.Pro422Ser (c.1264C>T) in the general population?

AGBL5 p.Pro422Ser (c.1264C>T) is very rare (popmax 0.01%, amr) (gnomAD).

What do computational predictors say about AGBL5 p.Pro422Ser (c.1264C>T)?

AlphaMissense predicts likely benign (score 0.2712) — an in-silico prediction, not a clinical call.

AGBL5 p.Pro422Ser

c.1264C>T · rs187389989 · VCV1439290

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2712 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.01%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2712	likely benign
REVEL	0.205	benign-leaning
SaProt	LLR -6.89	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 7.7	GERP 2.5, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 4,357 bp · p 1.1e-07 · regional, not allelic
Overall
CADD	25.6	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 0.01% Admixed American · 6/60,008 alleles

Filtering AF 0.00428% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00295%

Overall 0.000867% 14/1,614,096 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.01%	10,001
Remaining individualsnot grpmax-eligible	0.0048%	20,830
East Asian	0.00445%	22,452
European (non-Finnish)	0.000254%	393,349

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.Pro422Ser
Coding: c.1264C>T
MANE Select: NM_021831
dbSNP: rs187389989
Type: single nucleotide variant
Location: chr2:27056037 (GRCh38)
Gene constraint: LOEUF 0.709 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.36 · 10 PDB
Residue 422: 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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

AGBL5 p.Pro422Ala Uncertain significance ★★ ⚠ same residue
AGBL5 p.Pro422Thr Uncertain significance ★★ ⚠ same residue
AGBL5 p.Pro422Arg Uncertain significance ★★ ⚠ same residue
AGBL5 p.Pro422His Uncertain significance ★★ ⚠ same residue
AGBL5 p.Pro422Leu Uncertain significance ★★ ⚠ same residue
AGBL5 p.Pro422= Likely benign ★ same residue
AGBL5 p.Ala530Thr Uncertain significance ★★ ⚠ same condition
AGBL5 p.Arg111Cys 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-pro422ser (accessed [today's date]).

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