Is BSPRY p.Pro93Leu (c.278C>T) pathogenic?

BSPRY p.Pro93Leu (c.278C>T) is classified Uncertain significance in BSPRY (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-06). AlphaMissense: likely benign (0.212); Ultra-rare (popmax 0.0283%, amr).

How common is BSPRY p.Pro93Leu (c.278C>T) in the general population?

BSPRY p.Pro93Leu (c.278C>T) is ultra-rare (popmax 0.0283%, amr) (gnomAD).

What do computational predictors say about BSPRY p.Pro93Leu (c.278C>T)?

AlphaMissense predicts likely benign (score 0.212) — an in-silico prediction, not a clinical call.

BSPRY p.Pro93Leu

c.278C>T · rs368306479 · VCV3135317

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.212 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0283%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.212	likely benign
REVEL	0.039	moderately benign-leaning
SaProt	LLR -12.14	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3	GERP 0.55, phastCons 0.99
Regional constraint	o/e 0.98	unconstrained · MANE · 21 kb · p 0.66 · regional, not allelic
Overall
CADD	21.5	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

Grpmax group 0.0283% Admixed American · 17/59,990 alleles

Filtering AF 0.018% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0147%

Overall 0.00384% 62/1,613,840 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0283%	3,529
Remaining individualsnot grpmax-eligible	0.0128%	7,810
East Asian	0.00446%	22,444
South Asian	0.00439%	22,769
African / African-American	0.00267%	37,451
European (non-Finnish)	0.00246%	40,685

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.Pro93Leu
Coding: c.278C>T
MANE Select: NM_017688
dbSNP: rs368306479
Type: single nucleotide variant
Location: chr9:113354316 (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.Ala45Gly Uncertain significance ★ ⚠ same type
BSPRY p.Ala82Val Uncertain significance ★ ⚠ same type
BSPRY p.Arg113Trp 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-pro93leu (accessed [today's date]).

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