Is ALPL p.Arg71His (c.212G>A) pathogenic?

ALPL p.Arg71His (c.212G>A) is classified Pathogenic in ALPL (ClinVar, Multiple submitters, 10 submitters; last evaluated 2026-08-06). AlphaMissense: likely pathogenic (0.871); Very rare (popmax 0.00167%, amr); Associated with hypophosphatasia.

What condition is associated with ALPL p.Arg71His (c.212G>A)?

ALPL p.Arg71His (c.212G>A) is associated with hypophosphatasia, adult hypophosphatasia, childhood hypophosphatasia (ClinVar).

How common is ALPL p.Arg71His (c.212G>A) in the general population?

ALPL p.Arg71His (c.212G>A) is very rare (popmax 0.00167%, amr) (gnomAD).

How is Hypophosphatasia inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about ALPL p.Arg71His (c.212G>A)?

AlphaMissense predicts likely pathogenic (score 0.871) — an in-silico prediction, not a clinical call.

ALPL p.Arg71His

c.212G>A · rs121918003 · VCV1070177

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

AlphaMissense

likely pathogenic

0.871 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hypophosphatasia

Computational evidence

Protein change
AlphaMissense	0.871	likely pathogenic ✓ concordant with ClinVar
REVEL	0.975	strongly pathogenic-leaning
SaProt	LLR -15.27	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.26 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 24 kb · p 6.1e-06 · regional, not allelic
Overall
CADD	33.0	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 0.00167% Admixed American · 1/59,872 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000496% 8/1,612,650 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,872
European (non-Finnish)	0.000593%	168,509

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.Arg71His
Coding: c.212G>A
MANE Select: NM_000478
dbSNP: rs121918003
Type: single nucleotide variant
Location: chr1:21561127 (GRCh38)
Gene constraint: LOEUF 0.987 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.74 · 5 PDB
Residue 71: an α-helix; a UniProt-annotated variant site (in hops; abolished alkaline phosphatase activity); a UniProt-annotated variant site (in hops; loss of alkaline phosphatase activity); a UniProt-annotated variant site (in hppc; severe allele)

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

Disease context

hypophosphatasia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: adult hypophosphatasia childhood hypophosphatasia infantile hypophosphatasia

For Hypophosphatasia (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: All ages

Similar variants

ALPL p.Arg71Cys Pathogenic ★★ same residue
ALPL p.Arg71Gly Pathogenic/Likely pathogenic ★★ same residue
ALPL p.Arg71Pro Pathogenic/Likely pathogenic ★★ same residue
ALPL p.Arg71Ser Pathogenic/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

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-arg71his (accessed [today's date]).

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