Is BBC3 p.Ala114Pro (c.340G>C) pathogenic?

BBC3 p.Ala114Pro (c.340G>C) is classified Uncertain significance in BBC3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-16). AlphaMissense: likely benign (0.1437); Rare (popmax 0.1%, afr).

How common is BBC3 p.Ala114Pro (c.340G>C) in the general population?

BBC3 p.Ala114Pro (c.340G>C) is rare (popmax 0.1%, afr) (gnomAD).

What do computational predictors say about BBC3 p.Ala114Pro (c.340G>C)?

AlphaMissense predicts likely benign (score 0.1437) — an in-silico prediction, not a clinical call.

BBC3 p.Ala114Pro

c.340G>C · VCV4827971

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1437 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.1%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1437	likely benign
REVEL	0.12	moderately benign-leaning
SaProt	LLR -6.53	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 2.9	GERP 4.2, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 6,626 bp · p 0.0062 · regional, not allelic
Overall
CADD	23.1	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM G148A vs ClinVar A114P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.1% African / African-American · 69/68,666 alleles

Filtering AF 0.0814% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0745%

Overall 0.00699% 104/1,488,398 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.1%	995
Middle Eastern	0.0806%	1,241
Remaining individualsnot grpmax-eligible	0.0175%	5,729
Admixed American	0.00712%	14,049
European (non-Finnish)	0.00161%	62,299

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.Ala114Pro
Coding: c.340G>C
MANE Select: NM_014417
Type: single nucleotide variant
Location: chr19:47226689 (GRCh38)
Gene constraint: LOEUF 1.293 · pLI 0.05 (gnomAD)
Structure: AlphaFold pLDDT 47.60 · 13 PDB
Residue 114: 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-ala114pro (accessed [today's date]).

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