Is AP1G2 p.Gly447Trp (c.1339G>T) pathogenic?

AP1G2 p.Gly447Trp (c.1339G>T) is classified Uncertain significance in AP1G2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-18). AlphaMissense: ambiguous (0.4648); Ultra-rare (popmax 0.0867%, amr).

How common is AP1G2 p.Gly447Trp (c.1339G>T) in the general population?

AP1G2 p.Gly447Trp (c.1339G>T) is ultra-rare (popmax 0.0867%, amr) (gnomAD).

What do computational predictors say about AP1G2 p.Gly447Trp (c.1339G>T)?

AlphaMissense predicts ambiguous (score 0.4648) — an in-silico prediction, not a clinical call.

AP1G2 p.Gly447Trp

c.1339G>T · VCV3922064

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4648 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0867%, amr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4648	ambiguous
REVEL	0.218	benign-leaning
SaProt	LLR -11.89	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 1.2, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 7,562 bp · p 0.22 · regional, not allelic
Overall
CADD	24.3	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 0.0867% Admixed American · 52/59,980 alleles

Filtering AF 0.0679% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0611%

Overall 0.0397% 640/1,613,682 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0867%	1,153
European (non-Finnish)	0.0475%	2,103
Remaining individualsnot grpmax-eligible	0.0272%	3,675
Middle Eastern	0.0167%	5,980
African / African-American	0.00933%	10,721
Finnishnot grpmax-eligible	0.00312%	32,004

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.Gly447Trp
Coding: c.1339G>T
MANE Select: NM_003917
Type: single nucleotide variant
Location: chr14:23563451 (GRCh38)
Gene constraint: LOEUF 1.004 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.13 · 4 PDB

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-gly447trp (accessed [today's date]).

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