Is BSPRY p.Arg268Cys (c.802C>T) pathogenic?

BSPRY p.Arg268Cys (c.802C>T) is classified Uncertain significance in BSPRY (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-29). AlphaMissense: likely benign (0.2517); Very rare (popmax 0.004%, afr).

How common is BSPRY p.Arg268Cys (c.802C>T) in the general population?

BSPRY p.Arg268Cys (c.802C>T) is very rare (popmax 0.004%, afr) (gnomAD).

What do computational predictors say about BSPRY p.Arg268Cys (c.802C>T)?

AlphaMissense predicts likely benign (score 0.2517) — an in-silico prediction, not a clinical call.

BSPRY p.Arg268Cys

c.802C>T · VCV4216580

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2517 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.004%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2517	likely benign
REVEL	0.676	pathogenic-leaning
SaProt	LLR -13.36	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 2.2, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 21 kb · p 0.66 · regional, not allelic
Overall
CADD	28.1	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 0.004% African / African-American · 3/74,940 alleles

Filtering AF 0.00247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00217%

Overall 0.00297% 48/1,614,108 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.004%	24,980
European (non-Finnish)	0.0033%	30,258
South Asian	0.00329%	30,363
Remaining individualsnot grpmax-eligible	0.0032%	31,244
Admixed American	0.00167%	60,006

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.Arg268Cys
Coding: c.802C>T
MANE Select: NM_017688
Type: single nucleotide variant
Location: chr9:113369735 (GRCh38)
Gene constraint: LOEUF 1.216 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.75
Residue 268: the b30.2/spry domain

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-arg268cys (accessed [today's date]).

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