Is AGBL4 p.Glu458Asp (c.1374A>T) pathogenic?

AGBL4 p.Glu458Asp (c.1374A>T) is classified Uncertain significance in AGBL4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-29). AlphaMissense: likely benign (0.0699); Very rare (popmax 0.00061%, nfe).

How common is AGBL4 p.Glu458Asp (c.1374A>T) in the general population?

AGBL4 p.Glu458Asp (c.1374A>T) is very rare (popmax 0.00061%, nfe) (gnomAD).

What do computational predictors say about AGBL4 p.Glu458Asp (c.1374A>T)?

AlphaMissense predicts likely benign (score 0.0699) — an in-silico prediction, not a clinical call.

AGBL4 p.Glu458Asp

c.1374A>T · VCV4250955

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0699 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00061%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0699	likely benign
REVEL	0.032	moderately benign-leaning
SaProt	LLR -6.43	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 -0.23	GERP 1.1
Regional constraint	o/e 0.92	unconstrained · MANE · 1,490 kb · p 0.038 · regional, not allelic
Overall
CADD	12.38	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 0.00061% European (non-Finnish) · 7/1,146,814 alleles

Filtering AF 0.000254% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000163%

Overall 0.000451% 7/1,551,350 alleles · very rare

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.Glu458Asp
Coding: c.1374A>T
MANE Select: NM_032785
Type: single nucleotide variant
Location: chr1:48534907 (GRCh38)
Gene constraint: LOEUF 1.107 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.59

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

Similar variants

AGBL4 p.Ala480Gly Uncertain significance ★ ⚠ same type
AGBL4 p.Ala480Val Uncertain significance ★ ⚠ same type
AGBL4 p.Arg258Gln Uncertain significance ★ ⚠ same type
AGBL4 p.Arg348Gln Uncertain significance ★ ⚠ same type
AGBL4 p.Arg348Trp 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

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-glu458asp (accessed [today's date]).

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