Is ALPL p.Ala9Val (c.26C>T) pathogenic?

ALPL p.Ala9Val (c.26C>T) is classified Uncertain significance in ALPL (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-07-04). AlphaMissense: likely benign (0.0928); Very rare (popmax 0.0042%, nfe); Associated with adult hypophosphatasia.

What condition is associated with ALPL p.Ala9Val (c.26C>T)?

ALPL p.Ala9Val (c.26C>T) is associated with adult hypophosphatasia, hypophosphatasia, childhood hypophosphatasia (ClinVar).

How common is ALPL p.Ala9Val (c.26C>T) in the general population?

ALPL p.Ala9Val (c.26C>T) is very rare (popmax 0.0042%, nfe) (gnomAD).

What do computational predictors say about ALPL p.Ala9Val (c.26C>T)?

AlphaMissense predicts likely benign (score 0.0928) — an in-silico prediction, not a clinical call.

ALPL p.Ala9Val

c.26C>T · rs772679576 · VCV876665

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0928 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0042%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

adult hypophosphatasia

Computational evidence

Protein change
AlphaMissense	0.0928	likely benign
REVEL	0.25	benign-leaning
SaProt	LLR -5.52	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.7	GERP 0.5, phastCons 0.99
Regional constraint	o/e 0.83	unconstrained · MANE · 24 kb · p 6.1e-06 · regional, not allelic
Overall
CADD	17.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0042% European (non-Finnish) · 49/1,167,680 alleles

Filtering AF 0.00321% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00289%

Overall 0.00327% 52/1,592,572 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0042%	23,830
Remaining individualsnot grpmax-eligible	0.00164%	61,102
African / African-American	0.00135%	73,944
South Asian	0.0011%	90,728

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.Ala9Val
Coding: c.26C>T
MANE Select: NM_000478
dbSNP: rs772679576
Type: single nucleotide variant
Location: chr1:21554107 (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: hypophosphatasia childhood hypophosphatasia infantile hypophosphatasia

Similar variants

ALPL p.Ala9Ser Uncertain significance ★ ⚠ same residue
ALPL p.Ala9= Likely benign ★ 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

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-ala9val (accessed [today's date]).

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