Is ALPL p.Ala177Ser (c.529G>T) pathogenic?

ALPL p.Ala177Ser (c.529G>T) is classified Likely pathogenic in ALPL (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-29). AlphaMissense: likely benign (0.1189); Very rare (popmax 8.47e-05%, nfe).

How common is ALPL p.Ala177Ser (c.529G>T) in the general population?

ALPL p.Ala177Ser (c.529G>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about ALPL p.Ala177Ser (c.529G>T)?

AlphaMissense predicts likely benign (score 0.1189) — an in-silico prediction, not a clinical call.

ALPL p.Ala177Ser

c.529G>T · rs199669988 · VCV2782530

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1189 · ACMG-weighted

gnomAD v4.1

Rare

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

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1189	likely benign ⚠ discordant with ClinVar
REVEL	0.446	indeterminate
SaProt	LLR -7.58	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 0.2	GERP -3.6, phastCons 0.002
Regional constraint	o/e 0.83	unconstrained · MANE · 24 kb · p 6.1e-06 · regional, not allelic
Overall
CADD	5.185	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) · 1/1,179,996 alleles

Overall 6.84e-05% 1/1,461,756 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.Ala177Ser
Coding: c.529G>T
MANE Select: NM_000478
dbSNP: rs199669988
Type: single nucleotide variant
Location: chr1:21564097 (GRCh38)
Gene constraint: LOEUF 0.987 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.74 · 5 PDB
Residue 177: a turn; a disulfide bond; a UniProt-annotated variant site (in hops and hppc; moderate allele; normal alkaline phosphatase activity toward diphosphate and increased activity toward pyridoxal 5'-phosphate)

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

Similar variants

ALPL p.Ala177Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
ALPL p.Ala177Val Conflicting classifications of pathogenicity ★ ⚠ same residue
ALPL p.Ala177= Likely benign ★ same residue
ALPL c.1190-2A>T Pathogenic ★★ same type
ALPL c.182-1G>A Pathogenic/Likely pathogenic ★★ same type
ALPL c.182-2A>G Pathogenic/Likely pathogenic ★★ same type
ALPL c.297+1G>A Pathogenic/Likely pathogenic ★★ same type
ALPL c.298-1G>A Pathogenic ★★ same type

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-ala177ser (accessed [today's date]).

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