Is APPL1 p.Pro268Arg (c.803C>G) pathogenic?

APPL1 p.Pro268Arg (c.803C>G) is classified Uncertain significance in APPL1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-30). AlphaMissense: likely benign (0.1337); Very rare (popmax 0.00237%, nfe).

How common is APPL1 p.Pro268Arg (c.803C>G) in the general population?

APPL1 p.Pro268Arg (c.803C>G) is very rare (popmax 0.00237%, nfe) (gnomAD).

What do computational predictors say about APPL1 p.Pro268Arg (c.803C>G)?

AlphaMissense predicts likely benign (score 0.1337) — an in-silico prediction, not a clinical call.

APPL1 p.Pro268Arg

c.803C>G · rs373408408 · VCV2603143

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1337 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00237%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1337	likely benign
REVEL	0.042	moderately benign-leaning
SaProt	LLR -6.72	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 3.3	GERP 2, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 42 kb · p 0.0023 · regional, not allelic
Overall
CADD	22.0	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 0.00237% European (non-Finnish) · 28/1,180,034 alleles

Filtering AF 0.00164% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00142%

Overall 0.0018% 29/1,613,948 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00237%	42,144
Remaining individualsnot grpmax-eligible	0.0016%	62,480

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.Pro268Arg
Coding: c.803C>G
MANE Select: NM_012096
dbSNP: rs373408408
Type: single nucleotide variant
Location: chr3:57248291 (GRCh38)
Gene constraint: LOEUF 0.524 · pLI 0.88 (gnomAD)
Structure: AlphaFold pLDDT 81.44 · 8 PDB
Residue 268: the bar domain; a turn; the 'required for rab5a binding' region

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

Similar variants

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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-pro268arg (accessed [today's date]).

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