Is GNPTAB p.Pro696Arg (c.2087C>G) pathogenic?

GNPTAB p.Pro696Arg (c.2087C>G) is classified Uncertain significance in GNPTAB (ClinVar, No assertion criteria, 1 submitter; last evaluated 2025-01-21). AlphaMissense: likely benign (0.2764); Very rare (popmax 6.2e-05%); Associated with mucolipidosis type II.

What condition is associated with GNPTAB p.Pro696Arg (c.2087C>G)?

GNPTAB p.Pro696Arg (c.2087C>G) is associated with mucolipidosis type II (ClinVar).

How common is GNPTAB p.Pro696Arg (c.2087C>G) in the general population?

GNPTAB p.Pro696Arg (c.2087C>G) is very rare (popmax 6.2e-05%) (gnomAD).

How is Mucolipidosis type II inherited?

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

What do computational predictors say about GNPTAB p.Pro696Arg (c.2087C>G)?

AlphaMissense predicts likely benign (score 0.2764) — an in-silico prediction, not a clinical call.

GNPTAB p.Pro696Arg

c.2087C>G · VCV4068866

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2764 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.2e-05%)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

mucolipidosis type II

Computational evidence

Protein change
AlphaMissense	0.2764	likely benign
REVEL	0.675	pathogenic-leaning
SaProt	LLR -7.23	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 9.8	GERP 1.9, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 84 kb · p 4.2e-05 · regional, not allelic
Overall
CADD	22.6	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 6.2e-05%

Overall 6.2e-05% 1/1,614,016 alleles · very rare exomes 1/1,461,800 · genomes 0/152,216 · joint denominator

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: GNPTAB
Protein: p.Pro696Arg
Coding: c.2087C>G
MANE Select: NM_024312
Type: single nucleotide variant
Location: chr12:101764830 (GRCh38)
Gene constraint: LOEUF 0.8 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.15 · 5 PDB
Residue 696: a UniProt-annotated variant site (in mliiia)

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

Disease context

mucolipidosis type II — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Mucolipidosis type II (Orphanet):

Inheritance: Autosomal recessive
Onset: Antenatal, Neonatal
Prevalence: 1-9 / 1 000 000 (Europe)

Similar variants

GNPTAB p.Pro696Leu Uncertain significance ★★ ⚠ same residue
GNPTAB p.Pro696= Likely benign ★ 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

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-pro696arg (accessed [today's date]).

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