Is ALPL p.Ala116Thr (c.346G>A) pathogenic?

ALPL p.Ala116Thr (c.346G>A) is classified Pathogenic in ALPL (ClinVar, Multiple submitters, 14 submitters; last evaluated 2025-11-28). AlphaMissense: likely pathogenic (0.9265); Very rare (popmax 0.0028%, nfe); Associated with ALPL-related disorder.

What condition is associated with ALPL p.Ala116Thr (c.346G>A)?

ALPL p.Ala116Thr (c.346G>A) is associated with ALPL-related disorder, odontohypophosphatasia, hypophosphatasia (ClinVar).

How common is ALPL p.Ala116Thr (c.346G>A) in the general population?

ALPL p.Ala116Thr (c.346G>A) is very rare (popmax 0.0028%, nfe) (gnomAD).

What do computational predictors say about ALPL p.Ala116Thr (c.346G>A)?

AlphaMissense predicts likely pathogenic (score 0.9265) — an in-silico prediction, not a clinical call.

ALPL p.Ala116Thr

c.346G>A · rs121918013 · VCV13677

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 14 submitters

AlphaMissense

likely pathogenic

0.9265 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0028%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ALPL-related disorder

Computational evidence

Protein change
AlphaMissense	0.9265	likely pathogenic ✓ concordant with ClinVar
REVEL	0.973	strongly pathogenic-leaning
SaProt	LLR -13.00	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 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 24 kb · p 6.1e-06 · regional, not allelic
Overall
CADD	32.0	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 0.0028% European (non-Finnish) · 33/1,180,018 alleles

Filtering AF 0.00199% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00175%

Overall 0.00246% 36/1,461,516 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0028%	35,758
East Asian	0.00223%	44,880
Finnishnot grpmax-eligible	0.00157%	63,694
South Asian	0.0011%	91,088

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.Ala116Thr
Coding: c.346G>A
MANE Select: NM_000478
dbSNP: rs121918013
Type: single nucleotide variant
Location: chr1:21563158 (GRCh38)
Gene constraint: LOEUF 0.987 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.74 · 5 PDB
Residue 116: an α-helix; a UniProt-annotated variant site (in hops; loss of alkaline phosphatase activity)

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

Disease context

ALPL-related disorder

Also linked: odontohypophosphatasia hypophosphatasia adult hypophosphatasia childhood hypophosphatasia infantile hypophosphatasia

Similar variants

ALPL p.Ala116Ser 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
ALPL c.62-1G>C 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-ala116thr (accessed [today's date]).

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