Is ALPL p.Ala33Pro (c.97G>C) pathogenic?

ALPL p.Ala33Pro (c.97G>C) is classified Conflicting classifications of pathogenicity in ALPL (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-04-25). AlphaMissense: likely pathogenic (0.9866); Absent from gnomAD v4.1; Associated with ALPL-related disorder.

What condition is associated with ALPL p.Ala33Pro (c.97G>C)?

ALPL p.Ala33Pro (c.97G>C) is associated with ALPL-related disorder (ClinVar).

How common is ALPL p.Ala33Pro (c.97G>C) in the general population?

ALPL p.Ala33Pro (c.97G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ALPL p.Ala33Pro (c.97G>C)?

AlphaMissense predicts likely pathogenic (score 0.9866) — an in-silico prediction, not a clinical call.

ALPL p.Ala33Pro

c.97G>C · rs1315428192 · VCV3251693

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9866 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ALPL-related disorder

Computational evidence

Protein change
AlphaMissense	0.9866	likely pathogenic · top 9% in ALPL
REVEL	0.912	moderately pathogenic-leaning
SaProt	LLR -13.84	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 12	GERP 0.67, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 24 kb · p 6.1e-06 · regional, not allelic
Overall
CADD	27.0	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

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: ALPL
Protein: p.Ala33Pro
Coding: c.97G>C
MANE Select: NM_000478
dbSNP: rs1315428192
Type: single nucleotide variant
Location: chr1:21560661 (GRCh38)
Gene constraint: LOEUF 0.987 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.74 · 5 PDB
Residue 33: an α-helix; a UniProt-annotated variant site (in hops; strongly reduced alkaline phosphatase activity)

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

Disease context

ALPL-related disorder

Similar variants

ALPL p.Ala33Val Pathogenic/Likely pathogenic ★★ same residue
ALPL p.Ala33Gly Conflicting classifications of pathogenicity ★ ⚠ same residue
ALPL p.Ala33= Likely benign ★ same residue
ALPL c.648+1G>A Pathogenic ★★ same condition
ALPL c.998-2A>G Likely pathogenic ★★ same condition
ALPL p.Ala114Thr Pathogenic ★★ same condition
ALPL p.Ala116Thr Pathogenic ★★ same condition
ALPL p.Ala176Thr Pathogenic/Likely pathogenic ★★ same condition

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-ala33pro (accessed [today's date]).

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