Is APPL1 p.Pro413= (c.1239A>G) pathogenic?

APPL1 p.Pro413= (c.1239A>G) is classified Likely benign in APPL1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-29). Very rare (popmax 0.005%, amr).

How common is APPL1 p.Pro413= (c.1239A>G) in the general population?

APPL1 p.Pro413= (c.1239A>G) is very rare (popmax 0.005%, amr) (gnomAD).

APPL1 p.Pro413=

c.1239A>G · VCV3618904

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.014	GERP -1.1, phastCons 0.019
Overall
CADD	5.643	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.005% Admixed American · 3/60,004 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.000248% 4/1,614,030 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	20,001
European (non-Finnish)	8.47e-05%	1,179,984

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: APPL1
Protein: p.Pro413=
Coding: c.1239A>G
MANE Select: NM_012096
Type: single nucleotide variant
Location: chr3:57257043 (GRCh38)
Gene constraint: LOEUF 0.524 · pLI 0.88 (gnomAD)
Structure: AlphaFold pLDDT 81.44 · 8 PDB
Residue 413: the 'required for rab5a binding' region; the 'disordered' region

Full APPL1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

APPL1 c.1658+6T>G Uncertain significance ★★ same type
APPL1 p.Arg275Gln Uncertain significance ★★ ⚠ same type
APPL1 p.Arg407Ser Uncertain significance ★★ ⚠ same type
APPL1 p.Arg412Trp Uncertain significance ★★ ⚠ same type
APPL1 p.Arg478Cys Uncertain significance ★★ ⚠ same type
APPL1 p.Arg526His Uncertain significance ★★ ⚠ same type
APPL1 p.Arg633His Uncertain significance ★★ ⚠ same type
APPL1 p.Arg72Cys 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/appl1-p-pro413 (accessed [today's date]).

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