Is ALPP p.Pro448Ser (c.1342C>T) pathogenic?

ALPP p.Pro448Ser (c.1342C>T) is classified Uncertain significance in ALPP (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-25). AlphaMissense: ambiguous (0.4451); Ultra-rare (popmax 0.025%, amr).

How common is ALPP p.Pro448Ser (c.1342C>T) in the general population?

ALPP p.Pro448Ser (c.1342C>T) is ultra-rare (popmax 0.025%, amr) (gnomAD).

What do computational predictors say about ALPP p.Pro448Ser (c.1342C>T)?

AlphaMissense predicts ambiguous (score 0.4451) — an in-silico prediction, not a clinical call.

ALPP p.Pro448Ser

c.1342C>T · rs765923696 · VCV2405002

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4451 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.025%, amr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4451	ambiguous
REVEL	0.661	pathogenic-leaning
SaProt	LLR -11.47	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.7	phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 469 bp · p 0.33 · regional, not allelic
Overall
CADD	24.0	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 0.025% Admixed American · 15/59,972 alleles

Filtering AF 0.0154% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0124%

Overall 0.0018% 29/1,613,106 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.025%	3,998
Remaining individualsnot grpmax-eligible	0.00961%	10,407
African / African-American	0.00133%	74,938
South Asian	0.0011%	90,924
European (non-Finnish)	0.000509%	196,643

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.Pro448Ser
Coding: c.1342C>T
MANE Select: NM_001632
dbSNP: rs765923696
Type: single nucleotide variant
Location: chr2:232381529 (GRCh38)
Gene constraint: LOEUF 1.117 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.73 · 8 PDB
Residue 448: the 'disordered' region

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-pro448ser (accessed [today's date]).

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