Is GNPTAB p.Phe995Ser (c.2984T>C) pathogenic?

GNPTAB p.Phe995Ser (c.2984T>C) is classified Uncertain significance in GNPTAB (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-19). AlphaMissense: likely pathogenic (0.9942); Absent from gnomAD v4.1; Associated with mucolipidosis type II.

What condition is associated with GNPTAB p.Phe995Ser (c.2984T>C)?

GNPTAB p.Phe995Ser (c.2984T>C) is associated with mucolipidosis type II, mucolipidosis type III, alpha/beta (ClinVar).

How common is GNPTAB p.Phe995Ser (c.2984T>C) in the general population?

GNPTAB p.Phe995Ser (c.2984T>C) is absent from gnomAD v4.1 (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.Phe995Ser (c.2984T>C)?

AlphaMissense predicts likely pathogenic (score 0.9942) — an in-silico prediction, not a clinical call.

GNPTAB p.Phe995Ser

c.2984T>C · rs1952988897 · VCV1046495

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9942 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

mucolipidosis type II

Computational evidence

Protein change
AlphaMissense	0.9942	likely pathogenic · top 5% in GNPTAB
REVEL	0.915	moderately pathogenic-leaning
SaProt	LLR -13.37	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 84 kb · p 4.2e-05 · regional, not allelic
Overall
CADD	27.8	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.Phe995Ser
Coding: c.2984T>C
MANE Select: NM_024312
dbSNP: rs1952988897
Type: single nucleotide variant
Location: chr12:101761278 (GRCh38)
Gene constraint: LOEUF 0.8 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.15 · 5 PDB
Residue 995: an α-helix; 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.Phe995= Likely benign ★ same residue
GNPTAB p.Phe995fs 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

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-phe995ser (accessed [today's date]).

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