Is BBC3 p.Pro42= (c.126C>T) pathogenic?

BBC3 p.Pro42= (c.126C>T) is classified Uncertain significance in BBC3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-23). AlphaMissense: likely benign (0.2934); Ultra-rare (popmax 0.0601%, amr).

How common is BBC3 p.Pro42= (c.126C>T) in the general population?

BBC3 p.Pro42= (c.126C>T) is ultra-rare (popmax 0.0601%, amr) (gnomAD).

What do computational predictors say about BBC3 p.Pro42= (c.126C>T)?

AlphaMissense predicts likely benign (score 0.2934) — an in-silico prediction, not a clinical call.

BBC3 p.Pro42=

c.126C>T · rs994270563 · VCV2596490

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2934 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0601%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2934	likely benign
REVEL	0.039	moderately benign-leaning
SaProt	LLR -8.72	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 -2.1	GERP -1.1
Overall
CADD	7.363	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 0.0601% Admixed American · 14/23,312 alleles

Filtering AF 0.0362% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.029%

Overall 0.00139% 17/1,223,456 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0601%	1,665
Remaining individualsnot grpmax-eligible	0.00444%	22,529
African / African-American	0.00157%	63,892

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: BBC3
Protein: p.Pro42=
Coding: c.126C>T
MANE Select: NM_014417
dbSNP: rs994270563
Type: single nucleotide variant
Location: chr19:47228306 (GRCh38)
Gene constraint: LOEUF 1.293 · pLI 0.05 (gnomAD)
Structure: AlphaFold pLDDT 47.60 · 13 PDB
Residue 42: the 'disordered' region

Full BBC3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BBC3 c.*23C>T Benign/Likely benign ★★ same type
BBC3 c.-3G>A Uncertain significance ★ ⚠ same type
BBC3 c.*16C>T Uncertain significance ★ ⚠ same type
BBC3 c.*46C>T Uncertain significance ★ ⚠ same type
BBC3 c.*57C>T Uncertain significance ★ ⚠ same type
BBC3 c.*64C>G Uncertain significance ★ ⚠ same type
BBC3 c.*76C>G Uncertain significance ★ ⚠ same type
BBC3 c.*79G>T 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/bbc3-p-pro42 (accessed [today's date]).

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