Is ALPL p.Met1Val (c.1A>G) pathogenic?

ALPL p.Met1Val (c.1A>G) is classified Pathogenic/Likely pathogenic in ALPL (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-04-19). Absent from gnomAD v4.1; Associated with adult hypophosphatasia.

What condition is associated with ALPL p.Met1Val (c.1A>G)?

ALPL p.Met1Val (c.1A>G) is associated with adult hypophosphatasia, childhood hypophosphatasia, infantile hypophosphatasia (ClinVar).

How common is ALPL p.Met1Val (c.1A>G) in the general population?

ALPL p.Met1Val (c.1A>G) is absent from gnomAD v4.1 (gnomAD).

ALPL p.Met1Val

c.1A>G · rs2148135255 · VCV1382079

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

start-loss

predicted LoF

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

adult hypophosphatasia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	start-loss	predicted loss-of-function
REVEL	0.554	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.6, phastCons 1
Overall
CADD	19.21	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

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.Met1Val
Coding: c.1A>G
MANE Select: NM_000478
dbSNP: rs2148135255
Type: single nucleotide variant
Location: chr1:21554082 (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

Disease context

adult hypophosphatasia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: childhood hypophosphatasia infantile hypophosphatasia

Similar variants

ALPL p.Met1Thr Pathogenic/Likely pathogenic ★★ same residue
ALPL p.Met1Ile Pathogenic ★ same residue
ALPL c.1190-2A>T Pathogenic ★★ same condition
ALPL c.298-1G>A Pathogenic ★★ same condition
ALPL c.62-1G>C Pathogenic/Likely pathogenic ★★ same condition
ALPL c.648+1G>A Pathogenic ★★ same condition
ALPL c.648+1G>T Pathogenic ★★ same condition
ALPL c.649-1G>A 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-met1val (accessed [today's date]).

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