Is BSPRY p.Ala45Gly (c.134C>G) pathogenic?

BSPRY p.Ala45Gly (c.134C>G) is classified Uncertain significance in BSPRY (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-19). AlphaMissense: likely benign (0.1315); Ultra-rare (popmax 0.0102%, nfe).

How common is BSPRY p.Ala45Gly (c.134C>G) in the general population?

BSPRY p.Ala45Gly (c.134C>G) is ultra-rare (popmax 0.0102%, nfe) (gnomAD).

What do computational predictors say about BSPRY p.Ala45Gly (c.134C>G)?

AlphaMissense predicts likely benign (score 0.1315) — an in-silico prediction, not a clinical call.

BSPRY p.Ala45Gly

c.134C>G · VCV4646847

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1315 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0102%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1315	likely benign
REVEL	0.052	moderately benign-leaning
SaProt	LLR -6.25	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.27	GERP -1.9
Regional constraint	o/e 0.98	unconstrained · MANE · 21 kb · p 0.66 · regional, not allelic
Overall
CADD	20.8	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 0.0102% European (non-Finnish) · 101/991,768 alleles

Filtering AF 0.00852% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00794%

Overall 0.00825% 102/1,236,302 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0102%	9,820
Remaining individualsnot grpmax-eligible	0.00222%	45,052

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: BSPRY
Protein: p.Ala45Gly
Coding: c.134C>G
MANE Select: NM_017688
Type: single nucleotide variant
Location: chr9:113349713 (GRCh38)
Gene constraint: LOEUF 1.216 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.75

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

Similar variants

BSPRY p.Gly373Ser Uncertain significance ★★ ⚠ same type
BSPRY p.Ala261Pro Uncertain significance ★ ⚠ same type
BSPRY p.Ala287Gly Uncertain significance ★ ⚠ same type
BSPRY p.Ala287Ser Uncertain significance ★ ⚠ same type
BSPRY p.Ala287Val Uncertain significance ★ ⚠ same type
BSPRY p.Ala82Val Uncertain significance ★ ⚠ same type
BSPRY p.Arg113Trp Uncertain significance ★ ⚠ same type
BSPRY p.Arg127Trp Uncertain significance ★ ⚠ same type

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/bspry-p-ala45gly (accessed [today's date]).

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