Is APPL2 p.Ile201Leu (c.601A>T) pathogenic?

APPL2 p.Ile201Leu (c.601A>T) is classified Likely benign in APPL2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-09). AlphaMissense: likely benign (0.0649); Absent from gnomAD v4.1.

How common is APPL2 p.Ile201Leu (c.601A>T) in the general population?

APPL2 p.Ile201Leu (c.601A>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about APPL2 p.Ile201Leu (c.601A>T)?

AlphaMissense predicts likely benign (score 0.0649) — an in-silico prediction, not a clinical call.

APPL2 p.Ile201Leu

c.601A>T · rs2499751918 · VCV3128093

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0649 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0649	likely benign
REVEL	0.054	moderately benign-leaning
SaProt	LLR -5.05	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>C here scores Δ0.98 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.035	GERP -1.6, phastCons 0.9
Regional constraint	o/e 0.89	unconstrained · MANE · 62 kb · p 0.0021 · regional, not allelic
Overall
CADD	5.584	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: APPL2
Protein: p.Ile201Leu
Coding: c.601A>T
MANE Select: NM_018171
dbSNP: rs2499751918
Type: single nucleotide variant
Location: chr12:105207081 (GRCh38)
Gene constraint: LOEUF 1.075 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.09 · 2 PDB
Residue 201: the bar domain; an α-helix; 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-ile201leu (accessed [today's date]).

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