Is ALPL p.Val95Met (c.283G>A) pathogenic?

ALPL p.Val95Met (c.283G>A) is classified Conflicting classifications of pathogenicity in ALPL (ClinVar, Conflicting submitters, 12 submitters; last evaluated 2026-05-28). AlphaMissense: likely benign (0.231); Ultra-rare (popmax 0.0329%, mid); Associated with hypophosphatasia.

What condition is associated with ALPL p.Val95Met (c.283G>A)?

ALPL p.Val95Met (c.283G>A) is associated with hypophosphatasia, osteogenesis imperfecta, adult hypophosphatasia (ClinVar).

How common is ALPL p.Val95Met (c.283G>A) in the general population?

ALPL p.Val95Met (c.283G>A) is ultra-rare (popmax 0.0329%, mid) (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.Val95Met (c.283G>A)?

AlphaMissense predicts likely benign (score 0.231) — an in-silico prediction, not a clinical call.

ALPL p.Val95Met

c.283G>A · rs139811782 · VCV427763

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 12 submitters

AlphaMissense

likely benign

0.231 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hypophosphatasia

Computational evidence

Protein change
AlphaMissense	0.231	likely benign
REVEL	0.761	pathogenic-leaning
SaProt	LLR -8.38	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.6	GERP -0.79, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 24 kb · p 6.1e-06 · regional, not allelic
Overall
CADD	27.3	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

Grpmax group 0.0329% Middle Eastern · 2/6,080 alleles

Filtering AF 0.0058% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00395%

Overall 0.00248% 40/1,610,548 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0329%	3,040
East Asian	0.0134%	7,455
Admixed American	0.00838%	11,930
Remaining individualsnot grpmax-eligible	0.00481%	20,784
South Asian	0.00222%	45,117
European (non-Finnish)	0.00187%	53,570

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.Val95Met
Coding: c.283G>A
MANE Select: NM_000478
dbSNP: rs139811782
Type: single nucleotide variant
Location: chr1:21561198 (GRCh38)
Gene constraint: LOEUF 0.987 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.74 · 5 PDB
Residue 95: 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: osteogenesis imperfecta adult hypophosphatasia childhood hypophosphatasia infantile hypophosphatasia

For Hypophosphatasia (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: All ages

Similar variants

ALPL p.Val95Glu 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-val95met (accessed [today's date]).

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