Is ALPP p.Ile300Phe (c.898A>T) pathogenic?

ALPP p.Ile300Phe (c.898A>T) is classified Uncertain significance in ALPP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-05). AlphaMissense: likely benign (0.1242); Very rare (popmax 0.00143%, afr).

How common is ALPP p.Ile300Phe (c.898A>T) in the general population?

ALPP p.Ile300Phe (c.898A>T) is very rare (popmax 0.00143%, afr) (gnomAD).

What do computational predictors say about ALPP p.Ile300Phe (c.898A>T)?

AlphaMissense predicts likely benign (score 0.1242) — an in-silico prediction, not a clinical call.

ALPP p.Ile300Phe

c.898A>T · VCV4640126

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1242 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00143%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1242	likely benign
REVEL	0.261	benign-leaning
SaProt	LLR -7.72	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 -4.1
Regional constraint	o/e 0.37	unconstrained · MANE · 179 bp · p 0.0032 · regional, not allelic
Overall
CADD	2.698	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 0.00143% African / African-American · 1/69,980 alleles

Overall 6.84e-05% 1/1,461,804 alleles · very rare

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.Ile300Phe
Coding: c.898A>T
MANE Select: NM_001632
Type: single nucleotide variant
Location: chr2:232380655 (GRCh38)
Gene constraint: LOEUF 1.117 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.73 · 8 PDB
Residue 300: 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-ile300phe (accessed [today's date]).

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