Is AGBL4 p.Arg348Trp (c.1042C>T) pathogenic?

AGBL4 p.Arg348Trp (c.1042C>T) is classified Uncertain significance in AGBL4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-13). AlphaMissense: likely pathogenic (0.6794); Ultra-rare (popmax 0.0493%, mid).

How common is AGBL4 p.Arg348Trp (c.1042C>T) in the general population?

AGBL4 p.Arg348Trp (c.1042C>T) is ultra-rare (popmax 0.0493%, mid) (gnomAD).

What do computational predictors say about AGBL4 p.Arg348Trp (c.1042C>T)?

AlphaMissense predicts likely pathogenic (score 0.6794) — an in-silico prediction, not a clinical call.

AGBL4 p.Arg348Trp

c.1042C>T · rs376731078 · VCV3095100

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6794 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0493%, mid)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6794	likely pathogenic
REVEL	0.293	indeterminate
SaProt	LLR -15.73	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.7	GERP 0.15, phastCons 0.99
Regional constraint	o/e 0.92	unconstrained · MANE · 1,490 kb · p 0.038 · regional, not allelic
Overall
CADD	27.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0493% Middle Eastern · 3/6,084 alleles

Filtering AF 0.0144% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0119%

Overall 0.00249% 40/1,608,334 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0493%	2,028
African / African-American	0.0227%	4,400
Admixed American	0.00337%	29,683
East Asian	0.00223%	44,782
Remaining individualsnot grpmax-eligible	0.0016%	62,340
European (non-Finnish)	0.00136%	73,600

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.Arg348Trp
Coding: c.1042C>T
MANE Select: NM_032785
dbSNP: rs376731078
Type: single nucleotide variant
Location: chr1:48590895 (GRCh38)
Gene constraint: LOEUF 1.107 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.59
Residue 348: the peptidase m14 domain

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

Similar variants

AGBL4 p.Arg348Gln Uncertain significance ★ ⚠ same residue
AGBL4 p.Ala480Gly Uncertain significance ★ ⚠ same type
AGBL4 p.Ala480Val Uncertain significance ★ ⚠ same type
AGBL4 p.Arg258Gln Uncertain significance ★ ⚠ same type
AGBL4 p.Arg351Ser Uncertain significance ★ ⚠ same type
AGBL4 p.Arg375Trp Uncertain significance ★ ⚠ same type
AGBL4 p.Arg385Cys Uncertain significance ★ ⚠ same type
AGBL4 p.Arg385Gly Uncertain significance ★ ⚠ 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/agbl4-p-arg348trp (accessed [today's date]).

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