Is BBC3 p.Leu115= (c.343C>T) pathogenic?

BBC3 p.Leu115= (c.343C>T) is classified Uncertain significance in BBC3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-15). AlphaMissense: likely benign (0.206); Ultra-rare (popmax 0.0115%, sas).

How common is BBC3 p.Leu115= (c.343C>T) in the general population?

BBC3 p.Leu115= (c.343C>T) is ultra-rare (popmax 0.0115%, sas) (gnomAD).

What do computational predictors say about BBC3 p.Leu115= (c.343C>T)?

AlphaMissense predicts likely benign (score 0.206) — an in-silico prediction, not a clinical call.

BBC3 p.Leu115=

c.343C>T · rs761068549 · VCV2467795

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.206 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0115%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.206	likely benign
REVEL	0.051	moderately benign-leaning
SaProt	LLR -9.48	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 6.5	GERP 3.1, phastCons 1
Overall
CADD	13.95	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 0.0115% South Asian · 9/78,492 alleles

Filtering AF 0.00598% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00439%

Overall 0.000744% 10/1,344,598 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0115%	8,721
Remaining individualsnot grpmax-eligible	0.00173%	57,722

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.Leu115=
Coding: c.343C>T
MANE Select: NM_014417
dbSNP: rs761068549
Type: single nucleotide variant
Location: chr19:47226686 (GRCh38)
Gene constraint: LOEUF 1.293 · pLI 0.05 (gnomAD)
Structure: AlphaFold pLDDT 47.60 · 13 PDB
Residue 115: 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-leu115 (accessed [today's date]).

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