Is ALPP p.Leu366Arg (c.1097T>G) pathogenic?

ALPP p.Leu366Arg (c.1097T>G) is classified Uncertain significance in ALPP (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-02). AlphaMissense: likely benign (0.176); Very rare (popmax 0.00477%, nfe).

How common is ALPP p.Leu366Arg (c.1097T>G) in the general population?

ALPP p.Leu366Arg (c.1097T>G) is very rare (popmax 0.00477%, nfe) (gnomAD).

What do computational predictors say about ALPP p.Leu366Arg (c.1097T>G)?

AlphaMissense predicts likely benign (score 0.176) — an in-silico prediction, not a clinical call.

ALPP p.Leu366Arg

c.1097T>G · VCV3533922

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.176 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00477%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.176	likely benign
REVEL	0.905	moderately pathogenic-leaning
SaProt	LLR -11.36	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	phastCons 1
Regional constraint	o/e 0.01	constrained · MANE · 594 bp · p 1.9e-31 · regional, not allelic
Overall
CADD	26.9	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 0.00477% European (non-Finnish) · 54/1,131,940 alleles

Filtering AF 0.00374% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00335%

Overall 0.00359% 55/1,530,456 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00477%	20,962
Remaining individualsnot grpmax-eligible	0.00169%	59,136

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: ALPP
Protein: p.Leu366Arg
Coding: c.1097T>G
MANE Select: NM_001632
Type: single nucleotide variant
Location: chr2:232380936 (GRCh38)
Gene constraint: LOEUF 1.117 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.73 · 8 PDB
Residue 366: an α-helix

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

Similar variants

ALPP c.865+8C>T Likely benign ★★ same type
ALPP p.Ala176= Benign ★★ same type
ALPP p.Arg231Pro Benign ★★ same type
ALPP p.Arg36= Benign ★★ same type
ALPP p.Glu37Gln Benign ★★ same type
ALPP p.Gly233= Likely benign ★★ same type
ALPP p.Gly63= Likely benign ★★ same type
ALPP p.Phe331= Benign ★★ 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/alpp-p-leu366arg (accessed [today's date]).

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