Is GNPTAB p.Pro655fs (c.1959_1960del) pathogenic?

GNPTAB p.Pro655fs (c.19591960del) is classified Pathogenic/Likely pathogenic in GNPTAB (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-01-12). Very rare (popmax 0.005%, amr); Associated with Inborn genetic diseases.

What condition is associated with GNPTAB p.Pro655fs (c.1959_1960del)?

GNPTAB p.Pro655fs (c.1959_1960del) is associated with Inborn genetic diseases, mucolipidosis type II, mucolipidosis type III, alpha/beta (ClinVar).

How common is GNPTAB p.Pro655fs (c.1959_1960del) in the general population?

GNPTAB p.Pro655fs (c.1959_1960del) is very rare (popmax 0.005%, amr) (gnomAD).

GNPTAB p.Pro655fs

c.1959_1960del · rs1429181351 · VCV520752

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 13 of 21
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 2.6	GERP -0.007, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.005% Admixed American · 3/60,010 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.000205% 3/1,461,798 alleles · very rare

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.Pro655fs
Coding: c.1959_1960del
MANE Select: NM_024312
dbSNP: rs1429181351
Type: Deletion
Location: chr12:101764957 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: mucolipidosis type II mucolipidosis type III, alpha/beta mucolipidosis

Similar variants

GNPTAB p.Pro655_Ile656insTer Pathogenic ★ same residue
GNPTAB p.Pro655Ser Uncertain significance ★★ ⚠ same residue
GNPTAB p.Pro655= Likely benign ★ same residue
GNPTAB c.2915+4_2915+9del Likely pathogenic ★★ same condition
GNPTAB p.Ala34fs Pathogenic/Likely pathogenic ★★ same condition
GNPTAB p.Asn1093_Cys1094insTer Pathogenic/Likely pathogenic ★★ same condition
GNPTAB p.Asn148fs Pathogenic ★★ same condition
GNPTAB p.Asp467fs 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-pro655fs (accessed [today's date]).

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