Is ALPL p.His210Arg (c.629A>G) pathogenic?

ALPL p.His210Arg (c.629A>G) is classified Likely pathogenic in ALPL (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-12-11). AlphaMissense: likely benign (0.1278); Very rare (popmax 0.000169%, nfe); Associated with ALPL-related disorder.

What condition is associated with ALPL p.His210Arg (c.629A>G)?

ALPL p.His210Arg (c.629A>G) is associated with ALPL-related disorder, hypophosphatasia, infantile hypophosphatasia (ClinVar).

How common is ALPL p.His210Arg (c.629A>G) in the general population?

ALPL p.His210Arg (c.629A>G) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about ALPL p.His210Arg (c.629A>G)?

AlphaMissense predicts likely benign (score 0.1278) — an in-silico prediction, not a clinical call.

ALPL p.His210Arg

c.629A>G · rs748031071 · VCV556859

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1278 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ALPL-related disorder

Computational evidence

Protein change
AlphaMissense	0.1278	likely benign ⚠ discordant with ClinVar
REVEL	0.903	moderately pathogenic-leaning
SaProt	LLR -8.87	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 9.2	GERP 0.61, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 24 kb · p 6.1e-06 · regional, not allelic
Overall
CADD	20.6	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 0.000169% European (non-Finnish) · 2/1,179,998 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,461,668 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.His210Arg
Coding: c.629A>G
MANE Select: NM_000478
dbSNP: rs748031071
Type: single nucleotide variant
Location: chr1:21564197 (GRCh38)
Gene constraint: LOEUF 0.987 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.74 · 5 PDB
Residue 210: an α-helix

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

Disease context

ALPL-related disorder

Also linked: hypophosphatasia infantile hypophosphatasia

Similar variants

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
ALPL c.648+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-his210arg (accessed [today's date]).

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