Is AGBL4 p.Arg375Gln (c.1124G>A) pathogenic?

AGBL4 p.Arg375Gln (c.1124G>A) is classified Benign in AGBL4 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-11-25). AlphaMissense: likely benign (0.1914); Rare (popmax 0.873%, afr); Associated with AGBL4-related disorder.

What condition is associated with AGBL4 p.Arg375Gln (c.1124G>A)?

AGBL4 p.Arg375Gln (c.1124G>A) is associated with AGBL4-related disorder (ClinVar).

How common is AGBL4 p.Arg375Gln (c.1124G>A) in the general population?

AGBL4 p.Arg375Gln (c.1124G>A) is rare (popmax 0.873%, afr) (gnomAD).

What do computational predictors say about AGBL4 p.Arg375Gln (c.1124G>A)?

AlphaMissense predicts likely benign (score 0.1914) — an in-silico prediction, not a clinical call.

AGBL4 p.Arg375Gln

c.1124G>A · rs138271641 · VCV3048435

Benign No assertion criteria

Classification

Benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1914 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.873%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

AGBL4-related disorder

Computational evidence

Protein change
AlphaMissense	0.1914	likely benign
REVEL	0.129	moderately benign-leaning
SaProt	LLR -11.23	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5	GERP 1.2, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 1,490 kb · p 0.038 · regional, not allelic
Overall
CADD	26.3	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 0.873% African / African-American · 640/73,296 alleles

Filtering AF 0.817% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.795%

Overall 0.0509% 792/1,555,520 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.873%	115
Admixed American	0.0801%	1,248
Remaining individualsnot grpmax-eligible	0.0762%	1,313
Middle Eastern	0.0167%	5,998
European (non-Finnish)	0.00531%	18,844
South Asian	0.00356%	28,063

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: AGBL4
Protein: p.Arg375Gln
Coding: c.1124G>A
MANE Select: NM_032785
dbSNP: rs138271641
Type: single nucleotide variant
Location: chr1:48587147 (GRCh38)
Gene constraint: LOEUF 1.107 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.59
Residue 375: the peptidase m14 domain

Full AGBL4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

AGBL4-related disorder

Similar variants

AGBL4 p.Arg375Trp Uncertain significance ★ ⚠ same residue
AGBL4 c.282+7G>A Likely benign same condition
AGBL4 c.594+8C>T Benign same condition
AGBL4 c.595-7T>G Likely benign same condition
AGBL4 c.725-4C>T Benign same condition
AGBL4 p.Arg215Gln Benign same condition
AGBL4 p.Gly232= Likely benign same condition
AGBL4 p.His142= Benign 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/agbl4-p-arg375gln (accessed [today's date]).

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