Is ALPL p.Val253Ile (c.757G>A) pathogenic?

ALPL p.Val253Ile (c.757G>A) is classified Uncertain significance in ALPL (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-09-01). AlphaMissense: likely benign (0.0951); Ultra-rare (popmax 0.0133%, afr); Associated with hypophosphatasia.

What condition is associated with ALPL p.Val253Ile (c.757G>A)?

ALPL p.Val253Ile (c.757G>A) is associated with hypophosphatasia (ClinVar).

How common is ALPL p.Val253Ile (c.757G>A) in the general population?

ALPL p.Val253Ile (c.757G>A) is ultra-rare (popmax 0.0133%, afr) (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.Val253Ile (c.757G>A)?

AlphaMissense predicts likely benign (score 0.0951) — an in-silico prediction, not a clinical call.

ALPL p.Val253Ile

c.757G>A · rs151270365 · VCV434139

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0951 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0133%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hypophosphatasia

Computational evidence

Protein change
AlphaMissense	0.0951	likely benign
REVEL	0.327	indeterminate
SaProt	LLR -5.24	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.19	GERP -2.9
Regional constraint	o/e 0.83	unconstrained · MANE · 24 kb · p 6.1e-06 · regional, not allelic
Overall
CADD	1.131	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 0.0133% African / African-American · 10/75,004 alleles

Filtering AF 0.00722% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00549%

Overall 0.00242% 39/1,614,026 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0133%	7,500
Ashkenazi Jewishnot grpmax-eligible	0.0101%	9,867
Remaining individualsnot grpmax-eligible	0.0048%	20,836
East Asian	0.00446%	22,425
European (non-Finnish)	0.00169%	59,000
South Asian	0.0011%	91,074

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.Val253Ile
Coding: c.757G>A
MANE Select: NM_000478
dbSNP: rs151270365
Type: single nucleotide variant
Location: chr1:21568212 (GRCh38)
Gene constraint: LOEUF 0.987 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.74 · 5 PDB
Residue 253: 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.Val253Leu Uncertain significance ★ ⚠ 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-val253ile (accessed [today's date]).

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