Is ALPL p.Pro466Ala (c.1396C>G) pathogenic?

ALPL p.Pro466Ala (c.1396C>G) is classified Likely pathogenic in ALPL (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-09). AlphaMissense: likely pathogenic (0.6848); Very rare (popmax 0.000593%, nfe).

How common is ALPL p.Pro466Ala (c.1396C>G) in the general population?

ALPL p.Pro466Ala (c.1396C>G) is very rare (popmax 0.000593%, nfe) (gnomAD).

What do computational predictors say about ALPL p.Pro466Ala (c.1396C>G)?

AlphaMissense predicts likely pathogenic (score 0.6848) — an in-silico prediction, not a clinical call.

ALPL p.Pro466Ala

c.1396C>G · rs1644754641 · VCV1968490

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6848 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000593%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6848	likely pathogenic ✓ concordant with ClinVar
REVEL	0.877	moderately pathogenic-leaning
SaProt	LLR -10.13	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 0.65, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 24 kb · p 6.1e-06 · regional, not allelic
Overall
CADD	28.3	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 0.000593% European (non-Finnish) · 7/1,179,936 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000435% 7/1,610,846 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: ALPL
Protein: p.Pro466Ala
Coding: c.1396C>G
MANE Select: NM_000478
dbSNP: rs1644754641
Type: single nucleotide variant
Location: chr1:21577469 (GRCh38)
Gene constraint: LOEUF 0.987 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.74 · 5 PDB

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

Similar variants

ALPL p.Pro466Arg Likely pathogenic ★ same residue
ALPL p.Pro466Leu Pathogenic ★ same residue
ALPL p.Pro466= Likely benign ★ same residue
ALPL c.1190-2A>T Pathogenic ★★ same type
ALPL c.182-1G>A Pathogenic/Likely pathogenic ★★ same type
ALPL c.182-2A>G Pathogenic/Likely pathogenic ★★ same type
ALPL c.297+1G>A Pathogenic/Likely pathogenic ★★ same type
ALPL c.298-1G>A Pathogenic ★★ 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/alpl-p-pro466ala (accessed [today's date]).

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