Is GNPTAB p.Ser15Pro (c.43T>C) pathogenic?

GNPTAB p.Ser15Pro (c.43T>C) is classified Uncertain significance in GNPTAB (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-06-22). AlphaMissense: likely pathogenic (0.9847); Absent from gnomAD v4.1; Associated with mucolipidosis type III, alpha/beta.

What condition is associated with GNPTAB p.Ser15Pro (c.43T>C)?

GNPTAB p.Ser15Pro (c.43T>C) is associated with mucolipidosis type III, alpha/beta, mucolipidosis type II (ClinVar).

How common is GNPTAB p.Ser15Pro (c.43T>C) in the general population?

GNPTAB p.Ser15Pro (c.43T>C) is absent from gnomAD v4.1 (gnomAD).

How is Mucolipidosis type III inherited?

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

What do computational predictors say about GNPTAB p.Ser15Pro (c.43T>C)?

AlphaMissense predicts likely pathogenic (score 0.9847) — an in-silico prediction, not a clinical call.

GNPTAB p.Ser15Pro

c.43T>C · rs2547989570 · VCV2444222

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9847 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

mucolipidosis type III, alpha/beta

Computational evidence

Protein change
AlphaMissense	0.9847	likely pathogenic · top 9% in GNPTAB
REVEL	0.582	indeterminate
SaProt	LLR -10.81	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>C here scores Δ0.34 · evaluated, not missing
Constraint at this position
Conservation	phyloP 8.6	GERP 1.3, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 84 kb · p 4.2e-05 · regional, not allelic
Overall
CADD	25.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: GNPTAB
Protein: p.Ser15Pro
Coding: c.43T>C
MANE Select: NM_024312
dbSNP: rs2547989570
Type: single nucleotide variant
Location: chr12:101830633 (GRCh38)
Gene constraint: LOEUF 0.8 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.15 · 5 PDB
Residue 15: a UniProt-annotated variant site (in mliiia; uncertain significance; no effect on protein abundance; decreased protein cleavage into alpha and beta subunits; decreased retention in the golgi; mistargeted to lysosomes and plasma membrane; decreased udp-n-acetylglucosamine-lysosomal-enzyme n-acetylglucosaminephosphotransferase activity)

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

Disease context

mucolipidosis type III, alpha/beta — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: mucolipidosis type II

For Mucolipidosis type III (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood
Prevalence: 1-9 / 1 000 000 (Europe)

Similar variants

GNPTAB p.Ser15Tyr Likely pathogenic ★ ⚠ same residue
GNPTAB c.118-1G>A Pathogenic/Likely pathogenic ★★ same condition
GNPTAB c.118-2A>G Pathogenic/Likely pathogenic ★★ same condition
GNPTAB c.1284+1G>T Pathogenic/Likely pathogenic ★★ same condition
GNPTAB c.1408+1G>T Pathogenic/Likely pathogenic ★★ same condition
GNPTAB c.1409-2A>G Pathogenic/Likely pathogenic ★★ same condition
GNPTAB c.2715+1G>A Pathogenic ★★ same condition
GNPTAB c.2715+2T>G 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/gnptab-p-ser15pro (accessed [today's date]).

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