Is APPL2 p.Gly352Arg (c.1054G>A) pathogenic?

APPL2 p.Gly352Arg (c.1054G>A) is classified Uncertain significance in APPL2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-08). AlphaMissense: likely pathogenic (0.7147); Ultra-rare (popmax 0.0296%, sas).

How common is APPL2 p.Gly352Arg (c.1054G>A) in the general population?

APPL2 p.Gly352Arg (c.1054G>A) is ultra-rare (popmax 0.0296%, sas) (gnomAD).

What do computational predictors say about APPL2 p.Gly352Arg (c.1054G>A)?

AlphaMissense predicts likely pathogenic (score 0.7147) — an in-silico prediction, not a clinical call.

APPL2 p.Gly352Arg

c.1054G>A · VCV3308855

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7147 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0296%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7147	likely pathogenic
REVEL	0.21	benign-leaning
SaProt	LLR -6.74	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 2.1, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 62 kb · p 0.0021 · regional, not allelic
Overall
CADD	25.4	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 0.0296% South Asian · 27/91,080 alleles

Filtering AF 0.0208% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.018%

Overall 0.00186% 30/1,614,126 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0296%	3,373
Remaining individualsnot grpmax-eligible	0.0032%	31,254
European (non-Finnish)	8.47e-05%	1,180,034

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: APPL2
Protein: p.Gly352Arg
Coding: c.1054G>A
MANE Select: NM_018171
Type: single nucleotide variant
Location: chr12:105195626 (GRCh38)
Gene constraint: LOEUF 1.075 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.09 · 2 PDB
Residue 352: the ph domain; a β-strand; the 'required for rab5a binding' region

Full APPL2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

APPL2 p.Ala136Thr Uncertain significance ★ ⚠ same type
APPL2 p.Ala145Val Uncertain significance ★ ⚠ same type
APPL2 p.Ala168Gly Uncertain significance ★ ⚠ same type
APPL2 p.Ala187Thr Uncertain significance ★ ⚠ same type
APPL2 p.Ala445Thr Uncertain significance ★ ⚠ same type
APPL2 p.Ala445Val Uncertain significance ★ ⚠ same type
APPL2 p.Ala503Val Uncertain significance ★ ⚠ same type
APPL2 p.Ala516Val 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/appl2-p-gly352arg (accessed [today's date]).

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