Is ALPL p.Thr48Ser (c.143C>G) pathogenic?

ALPL p.Thr48Ser (c.143C>G) is classified Uncertain significance in ALPL (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-15). AlphaMissense: likely benign (0.1305); Very rare (popmax 0.00167%, amr).

How common is ALPL p.Thr48Ser (c.143C>G) in the general population?

ALPL p.Thr48Ser (c.143C>G) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about ALPL p.Thr48Ser (c.143C>G)?

AlphaMissense predicts likely benign (score 0.1305) — an in-silico prediction, not a clinical call.

ALPL p.Thr48Ser

c.143C>G · VCV4737048

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1305 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1305	likely benign
REVEL	0.425	indeterminate
SaProt	LLR -5.20	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 4	GERP 1.8, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 24 kb · p 6.1e-06 · regional, not allelic
Overall
CADD	20.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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 · 1/60,010 alleles

Filtering AF 0.000878% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000717%

Overall 0.00123% 18/1,461,882 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,010
European (non-Finnish)	0.00144%	69,414

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.Thr48Ser
Coding: c.143C>G
MANE Select: NM_000478
Type: single nucleotide variant
Location: chr1:21560707 (GRCh38)
Gene constraint: LOEUF 0.987 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.74 · 5 PDB

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

Similar variants

ALPL p.Thr48Ile Uncertain significance ★ ⚠ 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
ALPL c.472+1G>A Pathogenic ★★ same type
ALPL c.62-1G>C Pathogenic/Likely 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-thr48ser (accessed [today's date]).

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