Is ALPL p.Val447Ala (c.1340T>C) pathogenic?

ALPL p.Val447Ala (c.1340T>C) is classified Conflicting classifications of pathogenicity in ALPL (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2021-03-16). AlphaMissense: likely pathogenic (0.7549); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with ALPL p.Val447Ala (c.1340T>C)?

ALPL p.Val447Ala (c.1340T>C) is associated with Inborn genetic diseases (ClinVar).

How common is ALPL p.Val447Ala (c.1340T>C) in the general population?

ALPL p.Val447Ala (c.1340T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ALPL p.Val447Ala (c.1340T>C)?

AlphaMissense predicts likely pathogenic (score 0.7549) — an in-silico prediction, not a clinical call.

ALPL p.Val447Ala

c.1340T>C · rs1570309482 · VCV1476990

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7549 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.7549	likely pathogenic
REVEL	0.891	moderately pathogenic-leaning
SaProt	LLR -10.35	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	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ALPL
Protein: p.Val447Ala
Coding: c.1340T>C
MANE Select: NM_000478
dbSNP: rs1570309482
Type: single nucleotide variant
Location: chr1:21577413 (GRCh38)
Gene constraint: LOEUF 0.987 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.74 · 5 PDB
Residue 447: a β-strand

Full ALPL gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ALPL p.Val447Leu Likely pathogenic ★★ same residue
ALPL p.Gly326Arg Pathogenic/Likely pathogenic ★★ same condition
ALPL p.Gly473Ser Pathogenic/Likely pathogenic ★★ ⚠ same condition
ALPL p.Arg138Trp Uncertain significance ★★ ⚠ same condition
ALPL p.Arg321Gln Uncertain significance ★★ ⚠ same condition
ALPL p.Asn47Lys Uncertain significance ★★ ⚠ same condition
ALPL p.Asp356Glu Uncertain significance ★★ ⚠ same condition
ALPL p.Gly11Asp Uncertain significance ★★ ⚠ 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-val447ala (accessed [today's date]).

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