Is ALPL p.Val217Ala (c.650T>C) pathogenic?

ALPL p.Val217Ala (c.650T>C) is classified Uncertain significance in ALPL (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-09-01). AlphaMissense: likely pathogenic (0.9325); Very rare (popmax 0.00136%, nfe); Associated with hypophosphatasia.

What condition is associated with ALPL p.Val217Ala (c.650T>C)?

ALPL p.Val217Ala (c.650T>C) is associated with hypophosphatasia, adult hypophosphatasia, childhood hypophosphatasia (ClinVar).

How common is ALPL p.Val217Ala (c.650T>C) in the general population?

ALPL p.Val217Ala (c.650T>C) is very rare (popmax 0.00136%, nfe) (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.Val217Ala (c.650T>C)?

AlphaMissense predicts likely pathogenic (score 0.9325) — an in-silico prediction, not a clinical call.

ALPL p.Val217Ala

c.650T>C · rs777699004 · VCV1312292

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.9325 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00136%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hypophosphatasia

Computational evidence

Protein change
AlphaMissense	0.9325	likely pathogenic
REVEL	0.967	strongly pathogenic-leaning
SaProt	LLR -14.55	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 7.9	GERP 1.6, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 24 kb · p 6.1e-06 · regional, not allelic
Overall
CADD	31.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00136% European (non-Finnish) · 16/1,179,992 alleles

Filtering AF 0.000803% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00065%

Overall 0.00105% 17/1,613,798 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00136%	73,750
African / African-American	0.00134%	74,846

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.Val217Ala
Coding: c.650T>C
MANE Select: NM_000478
dbSNP: rs777699004
Type: single nucleotide variant
Location: chr1:21568105 (GRCh38)
Gene constraint: LOEUF 0.987 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.74 · 5 PDB
Residue 217: a β-strand

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

Also linked: adult hypophosphatasia childhood hypophosphatasia infantile hypophosphatasia

For Hypophosphatasia (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: All ages

Similar variants

ALPL p.Val217delinsAlaLys Pathogenic/Likely pathogenic ★★ same residue
ALPL p.Val217fs 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

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-val217ala (accessed [today's date]).

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