Is APPL1 p.Ile229Thr (c.686T>C) pathogenic?

APPL1 p.Ile229Thr (c.686T>C) is classified Uncertain significance in APPL1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-22). AlphaMissense: ambiguous (0.4774); Ultra-rare (popmax 0.0291%, eas).

How common is APPL1 p.Ile229Thr (c.686T>C) in the general population?

APPL1 p.Ile229Thr (c.686T>C) is ultra-rare (popmax 0.0291%, eas) (gnomAD).

What do computational predictors say about APPL1 p.Ile229Thr (c.686T>C)?

AlphaMissense predicts ambiguous (score 0.4774) — an in-silico prediction, not a clinical call.

APPL1 p.Ile229Thr

c.686T>C · rs745331742 · VCV2888229

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4774 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0291%, eas)

Computational evidence

Protein change
AlphaMissense	0.4774	ambiguous
REVEL	0.408	indeterminate
SaProt	LLR -8.49	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 42 kb · p 0.0023 · regional, not allelic
Overall
CADD	26.7	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 0.0291% East Asian · 13/44,706 alleles

Filtering AF 0.0172% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0136%

Overall 0.00118% 19/1,607,232 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0291%	3,439
Remaining individualsnot grpmax-eligible	0.00321%	31,115
South Asian	0.00221%	45,336
European (non-Finnish)	0.00017%	587,289

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.Ile229Thr
Coding: c.686T>C
MANE Select: NM_012096
dbSNP: rs745331742
Type: single nucleotide variant
Location: chr3:57247459 (GRCh38)
Gene constraint: LOEUF 0.524 · pLI 0.88 (gnomAD)
Structure: AlphaFold pLDDT 81.44 · 8 PDB
Residue 229: the bar domain; an α-helix; the 'required for rab5a binding' 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-ile229thr (accessed [today's date]).

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