Is ALPL p.Pro261Leu (c.782C>T) pathogenic?

ALPL p.Pro261Leu (c.782C>T) is classified Conflicting classifications of pathogenicity in ALPL (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-10-14). AlphaMissense: likely benign (0.2659); Very rare (popmax 0.00935%, afr); Associated with adult hypophosphatasia.

What condition is associated with ALPL p.Pro261Leu (c.782C>T)?

ALPL p.Pro261Leu (c.782C>T) is associated with adult hypophosphatasia, hypophosphatasia, childhood hypophosphatasia (ClinVar).

How common is ALPL p.Pro261Leu (c.782C>T) in the general population?

ALPL p.Pro261Leu (c.782C>T) is very rare (popmax 0.00935%, afr) (gnomAD).

What do computational predictors say about ALPL p.Pro261Leu (c.782C>T)?

AlphaMissense predicts likely benign (score 0.2659) — an in-silico prediction, not a clinical call.

ALPL p.Pro261Leu

c.782C>T · rs765149569 · VCV388169

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.2659 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00935%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

adult hypophosphatasia

Computational evidence

Protein change
AlphaMissense	0.2659	likely benign
REVEL	0.696	pathogenic-leaning
SaProt	LLR -10.78	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.3, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 24 kb · p 6.1e-06 · regional, not allelic
Overall
CADD	28.0	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

Grpmax group 0.00935% African / African-American · 7/74,876 alleles

Filtering AF 0.00438% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00309%

Overall 0.00266% 43/1,613,890 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00935%	10,697
European (non-Finnish)	0.00288%	34,706
Admixed American	0.00167%	59,990
Remaining individualsnot grpmax-eligible	0.0016%	62,488

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.Pro261Leu
Coding: c.782C>T
MANE Select: NM_000478
dbSNP: rs765149569
Type: single nucleotide variant
Location: chr1:21568237 (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.Pro261Gln Uncertain significance ★★ ⚠ same residue
ALPL p.Pro261Thr Uncertain significance ★★ ⚠ same residue
ALPL p.Pro261Ser Likely pathogenic ★ ⚠ same residue
ALPL p.Pro261= 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

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-pro261leu (accessed [today's date]).

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