Is GBA1 p.Leu135Pro (c.404T>C) pathogenic?

GBA1 p.Leu135Pro (c.404T>C) is classified Likely pathogenic in GBA1 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-25). AlphaMissense: likely pathogenic (0.9653); Absent from gnomAD v4.1; Associated with Gaucher disease.

What condition is associated with GBA1 p.Leu135Pro (c.404T>C)?

GBA1 p.Leu135Pro (c.404T>C) is associated with Gaucher disease (ClinVar).

How common is GBA1 p.Leu135Pro (c.404T>C) in the general population?

GBA1 p.Leu135Pro (c.404T>C) is absent from gnomAD v4.1 (gnomAD).

How is Gaucher disease inherited?

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

What do computational predictors say about GBA1 p.Leu135Pro (c.404T>C)?

AlphaMissense predicts likely pathogenic (score 0.9653) — an in-silico prediction, not a clinical call.

GBA1 p.Leu135Pro

c.404T>C · VCV4817758

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9653 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Gaucher disease

Computational evidence

Protein change
AlphaMissense	0.9653	likely pathogenic ✓ concordant with ClinVar · top 9% in GBA1
REVEL	0.909	moderately pathogenic-leaning
SaProt	LLR -16.24	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.6, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 2,520 bp · p 0.053 · regional, not allelic
Overall
CADD	28.6	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

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: GBA1
Protein: p.Leu135Pro
Coding: c.404T>C
MANE Select: NM_000157
Type: single nucleotide variant
Location: chr1:155239666 (GRCh38)
Structure: AlphaFold pLDDT 93.46 · 58 PDB

Full GBA1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Gaucher disease — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Gaucher disease (Orphanet):

Inheritance: Autosomal recessive
Onset: All ages
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

GBA1 c.115+1G>A Pathogenic/Likely pathogenic ★★ same condition
GBA1 c.1388+1G>A Pathogenic ★★ same condition
GBA1 c.1505+2T>A Pathogenic/Likely pathogenic ★★ same condition
GBA1 c.762-1G>C Pathogenic/Likely pathogenic ★★ same condition
GBA1 p.Arg159Trp Pathogenic ★★ same condition
GBA1 p.Arg170Cys Pathogenic ★★ ⚠ same condition
GBA1 p.Arg170Leu Pathogenic/Likely pathogenic ★★ same condition
GBA1 p.Arg202Ter 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/gba1-p-leu135pro (accessed [today's date]).

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