Is AP1G2 p.His765Arg (c.2294A>G) pathogenic?

AP1G2 p.His765Arg (c.2294A>G) is classified Uncertain significance in AP1G2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-16). AlphaMissense: likely benign (0.0745); Ultra-rare (popmax 0.0367%, amr).

How common is AP1G2 p.His765Arg (c.2294A>G) in the general population?

AP1G2 p.His765Arg (c.2294A>G) is ultra-rare (popmax 0.0367%, amr) (gnomAD).

What do computational predictors say about AP1G2 p.His765Arg (c.2294A>G)?

AlphaMissense predicts likely benign (score 0.0745) — an in-silico prediction, not a clinical call.

AP1G2 p.His765Arg

c.2294A>G · rs573100612 · VCV3127455

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0745 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0367%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0745	likely benign
REVEL	0.087	moderately benign-leaning
SaProt	LLR -5.65	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 7.9	GERP 2.3, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 7,562 bp · p 0.22 · regional, not allelic
Overall
CADD	23.5	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 0.0367% Admixed American · 22/60,006 alleles

Filtering AF 0.0248% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0209%

Overall 0.00192% 31/1,614,012 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0367%	2,728
Remaining individualsnot grpmax-eligible	0.0032%	31,251
European (non-Finnish)	0.000593%	168,574

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: AP1G2
Protein: p.His765Arg
Coding: c.2294A>G
MANE Select: NM_003917
dbSNP: rs573100612
Type: single nucleotide variant
Location: chr14:23559813 (GRCh38)
Gene constraint: LOEUF 1.004 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.13 · 4 PDB
Residue 765: the gae domain; a β-strand

Full AP1G2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

AP1G2 p.Ala181Pro Uncertain significance ★ ⚠ same type
AP1G2 p.Ala360Thr Uncertain significance ★ ⚠ same type
AP1G2 p.Ala430Val Uncertain significance ★ ⚠ same type
AP1G2 p.Ala465Glu Uncertain significance ★ ⚠ same type
AP1G2 p.Ala508Thr Uncertain significance ★ ⚠ same type
AP1G2 p.Ala527Val Uncertain significance ★ ⚠ same type
AP1G2 p.Ala76Thr Uncertain significance ★ ⚠ same type
AP1G2 p.Arg137Gln 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/ap1g2-p-his765arg (accessed [today's date]).

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