Is ALPL p.Ala348Asp (c.1043C>A) pathogenic?

ALPL p.Ala348Asp (c.1043C>A) is classified Likely pathogenic in ALPL (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-29). AlphaMissense: likely pathogenic (0.9889); Absent from gnomAD v4.1; Associated with hypophosphatasia.

What condition is associated with ALPL p.Ala348Asp (c.1043C>A)?

ALPL p.Ala348Asp (c.1043C>A) is associated with hypophosphatasia (ClinVar).

How common is ALPL p.Ala348Asp (c.1043C>A) in the general population?

ALPL p.Ala348Asp (c.1043C>A) is absent from gnomAD v4.1 (gnomAD).

How is Hypophosphatasia inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about ALPL p.Ala348Asp (c.1043C>A)?

AlphaMissense predicts likely pathogenic (score 0.9889) — an in-silico prediction, not a clinical call.

ALPL p.Ala348Asp

c.1043C>A · VCV4086860

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9889 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hypophosphatasia

Computational evidence

Protein change
AlphaMissense	0.9889	likely pathogenic ✓ concordant with ClinVar · top 7% in ALPL
REVEL	0.902	moderately pathogenic-leaning
SaProt	LLR -16.84	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 7.7	GERP 1.6, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 24 kb · p 6.1e-06 · regional, not allelic
Overall
CADD	32.0	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.Ala348Asp
Coding: c.1043C>A
MANE Select: NM_000478
Type: single nucleotide variant
Location: chr1:21575778 (GRCh38)
Gene constraint: LOEUF 0.987 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.74 · 5 PDB
Residue 348: a UniProt-annotated variant site (in hops); an α-helix

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

Disease context

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

For Hypophosphatasia (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: All ages

Similar variants

ALPL p.Ala348Thr Pathogenic/Likely pathogenic ★★ same residue
ALPL c.1190-2A>T Pathogenic ★★ same condition
ALPL c.182-1G>A Pathogenic/Likely pathogenic ★★ same condition
ALPL c.182-2A>G Pathogenic/Likely pathogenic ★★ same condition
ALPL c.297+1G>A Pathogenic/Likely pathogenic ★★ same condition
ALPL c.298-1G>A Pathogenic ★★ same condition
ALPL c.472+1G>A Pathogenic ★★ same condition
ALPL c.62-1G>C 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-ala348asp (accessed [today's date]).

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