Is AGBL5 p.Arg142Cys (c.424C>T) pathogenic?

AGBL5 p.Arg142Cys (c.424C>T) is classified Uncertain significance in AGBL5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-09). AlphaMissense: ambiguous (0.3413); Very rare (popmax 0.00668%, eas); Associated with Inborn genetic diseases.

What condition is associated with AGBL5 p.Arg142Cys (c.424C>T)?

AGBL5 p.Arg142Cys (c.424C>T) is associated with Inborn genetic diseases (ClinVar).

How common is AGBL5 p.Arg142Cys (c.424C>T) in the general population?

AGBL5 p.Arg142Cys (c.424C>T) is very rare (popmax 0.00668%, eas) (gnomAD).

What do computational predictors say about AGBL5 p.Arg142Cys (c.424C>T)?

AlphaMissense predicts ambiguous (score 0.3413) — an in-silico prediction, not a clinical call.

AGBL5 p.Arg142Cys

c.424C>T · rs1476111182 · VCV2520502

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3413 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00668%, eas)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3413	ambiguous
REVEL	0.389	indeterminate
SaProt	LLR -9.43	tolerated
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.88 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.7	GERP 2.2, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 4,357 bp · p 1.1e-07 · regional, not allelic
Overall
CADD	33.0	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 0.00668% East Asian · 3/44,900 alleles

Filtering AF 0.00177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.00124% 20/1,613,964 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00668%	14,967
Finnishnot grpmax-eligible	0.00312%	32,016
Admixed American	0.00167%	59,988
European (non-Finnish)	0.00119%	84,284

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.Arg142Cys
Coding: c.424C>T
MANE Select: NM_021831
dbSNP: rs1476111182
Type: single nucleotide variant
Location: chr2:27053932 (GRCh38)
Gene constraint: LOEUF 0.709 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.36 · 10 PDB
Residue 142: a UniProt-annotated variant site (found in patients with a usher-like phenotype encompassing rp and hearing loss; likely pathogenic); a β-strand

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.Arg142= Likely benign ★ 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-arg142cys (accessed [today's date]).

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