Is ALPL p.Leu414Met (c.1240C>A) pathogenic?

ALPL p.Leu414Met (c.1240C>A) is classified Pathogenic/Likely pathogenic in ALPL (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-05-26). AlphaMissense: likely benign (0.2089); Very rare (popmax 8.47e-05%, nfe); Associated with adult hypophosphatasia.

What condition is associated with ALPL p.Leu414Met (c.1240C>A)?

ALPL p.Leu414Met (c.1240C>A) is associated with adult hypophosphatasia, hypophosphatasia (ClinVar).

How common is ALPL p.Leu414Met (c.1240C>A) in the general population?

ALPL p.Leu414Met (c.1240C>A) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about ALPL p.Leu414Met (c.1240C>A)?

AlphaMissense predicts likely benign (score 0.2089) — an in-silico prediction, not a clinical call.

ALPL p.Leu414Met

c.1240C>A · rs2148192444 · VCV1072423

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.2089 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

adult hypophosphatasia

Computational evidence

Protein change
AlphaMissense	0.2089	likely benign ⚠ discordant with ClinVar
REVEL	0.801	moderately pathogenic-leaning
SaProt	LLR -6.58	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 1.5	GERP 0.64, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 24 kb · p 6.1e-06 · regional, not allelic
Overall
CADD	21.3	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 8.47e-05% European (non-Finnish) · 1/1,179,952 alleles

Overall 6.84e-05% 1/1,461,802 alleles · very rare

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.Leu414Met
Coding: c.1240C>A
MANE Select: NM_000478
dbSNP: rs2148192444
Type: single nucleotide variant
Location: chr1:21576572 (GRCh38)
Gene constraint: LOEUF 0.987 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.74 · 5 PDB
Residue 414: a UniProt-annotated variant site (in hops; loss of alkaline phosphatase activity); a β-strand

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

Similar variants

ALPL p.Leu414Val Likely pathogenic ★★ ⚠ same residue
ALPL p.Leu414Pro 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

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-leu414met (accessed [today's date]).

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