Is GNPTAB p.Pro655Ser (c.1963C>T) pathogenic?

GNPTAB p.Pro655Ser (c.1963C>T) is classified Uncertain significance in GNPTAB (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-03-01). AlphaMissense: likely benign (0.0719); Very rare (popmax 0.00186%, nfe); Associated with mucolipidosis type II.

What condition is associated with GNPTAB p.Pro655Ser (c.1963C>T)?

GNPTAB p.Pro655Ser (c.1963C>T) is associated with mucolipidosis type II, mucolipidosis type III, alpha/beta (ClinVar).

How common is GNPTAB p.Pro655Ser (c.1963C>T) in the general population?

GNPTAB p.Pro655Ser (c.1963C>T) is very rare (popmax 0.00186%, nfe) (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.Pro655Ser (c.1963C>T)?

AlphaMissense predicts likely benign (score 0.0719) — an in-silico prediction, not a clinical call.

GNPTAB p.Pro655Ser

c.1963C>T · rs940673327 · VCV2228765

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0719 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00186%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

mucolipidosis type II

Computational evidence

Protein change
AlphaMissense	0.0719	likely benign
REVEL	0.337	indeterminate
SaProt	LLR -5.64	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 0.77	GERP -0.85, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 84 kb · p 4.2e-05 · regional, not allelic
Overall
CADD	7.092	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 0.00186% European (non-Finnish) · 22/1,179,982 alleles

Filtering AF 0.00122% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00143% 23/1,613,818 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00186%	53,635
Remaining individualsnot grpmax-eligible	0.0016%	62,484

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.Pro655Ser
Coding: c.1963C>T
MANE Select: NM_024312
dbSNP: rs940673327
Type: single nucleotide variant
Location: chr12:101764954 (GRCh38)
Gene constraint: LOEUF 0.8 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.15 · 5 PDB
Residue 655: 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

Also linked: mucolipidosis type III, alpha/beta

For Mucolipidosis type II (Orphanet):

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

Similar variants

GNPTAB p.Pro655= Likely benign ★ same residue
GNPTAB p.Pro655fs Pathogenic/Likely pathogenic ★★ same residue
GNPTAB p.Pro655_Ile656insTer 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

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-pro655ser (accessed [today's date]).

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