Is AGBL5 p.Pro185Ser (c.553C>T) pathogenic?

AGBL5 p.Pro185Ser (c.553C>T) is classified Conflicting classifications of pathogenicity in AGBL5 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-01-19). AlphaMissense: likely benign (0.0814); Ultra-rare (popmax 0.0364%, sas); Associated with Inborn genetic diseases.

What condition is associated with AGBL5 p.Pro185Ser (c.553C>T)?

AGBL5 p.Pro185Ser (c.553C>T) is associated with Inborn genetic diseases (ClinVar).

How common is AGBL5 p.Pro185Ser (c.553C>T) in the general population?

AGBL5 p.Pro185Ser (c.553C>T) is ultra-rare (popmax 0.0364%, sas) (gnomAD).

What do computational predictors say about AGBL5 p.Pro185Ser (c.553C>T)?

AlphaMissense predicts likely benign (score 0.0814) — an in-silico prediction, not a clinical call.

AGBL5 p.Pro185Ser

c.553C>T · rs185431140 · VCV1433084

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0814 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0364%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0814	likely benign
REVEL	0.053	moderately benign-leaning
SaProt	LLR -9.39	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 0.86	GERP -0.97, phastCons 0.99
Regional constraint	o/e 0.80	unconstrained · MANE · 4,357 bp · p 1.1e-07 · regional, not allelic
Overall
CADD	16.66	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 0.0364% South Asian · 33/90,776 alleles

Filtering AF 0.0266% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0232%

Overall 0.00732% 118/1,612,514 alleles · ultra-rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.113%	888
South Asiangrpmax	0.0364%	2,751
Remaining individualsnot grpmax-eligible	0.00961%	10,405
Admixed American	0.00167%	59,772
European (non-Finnish)	0.000509%	196,548

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro185Ser
Coding: c.553C>T
MANE Select: NM_021831
dbSNP: rs185431140
Type: single nucleotide variant
Location: chr2:27054631 (GRCh38)
Gene constraint: LOEUF 0.709 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.36 · 10 PDB
Residue 185: the peptidase m14 domain; a UniProt-annotated variant site (found in patients with a usher-like phenotype encompassing rp and hearing loss; likely pathogenic); an α-helix

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.Pro185Thr Uncertain significance ★ ⚠ same residue
AGBL5 p.Ala530Thr Uncertain significance ★★ ⚠ same condition
AGBL5 p.Arg111Cys Uncertain significance ★★ ⚠ same condition
AGBL5 p.Arg121His Uncertain significance ★★ ⚠ same condition
AGBL5 p.Arg147Cys Uncertain significance ★★ ⚠ same condition
AGBL5 p.Arg147Gly Uncertain significance ★★ ⚠ same condition
AGBL5 p.Arg147His Uncertain significance ★★ ⚠ same condition
AGBL5 p.Arg174His 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-pro185ser (accessed [today's date]).

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