Is BBC3 p.Ser33= (c.99G>C) pathogenic?

BBC3 p.Ser33= (c.99G>C) is classified Uncertain significance in BBC3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-25). AlphaMissense: ambiguous (0.4135); Ultra-rare (popmax 0.0172%, afr).

How common is BBC3 p.Ser33= (c.99G>C) in the general population?

BBC3 p.Ser33= (c.99G>C) is ultra-rare (popmax 0.0172%, afr) (gnomAD).

What do computational predictors say about BBC3 p.Ser33= (c.99G>C)?

AlphaMissense predicts ambiguous (score 0.4135) — an in-silico prediction, not a clinical call.

BBC3 p.Ser33=

c.99G>C · VCV3990020

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4135 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0172%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4135	ambiguous · top 10% in BBC3
REVEL	0.107	moderately benign-leaning
SaProt	LLR -5.79	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -4.6	GERP -0.42
Overall
CADD	8.007	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 0.0172% African / African-American · 11/64,042 alleles

Filtering AF 0.00958% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0074%

Overall 0.00122% 15/1,228,172 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0172%	5,822
Remaining individualsnot grpmax-eligible	0.0022%	45,428
European (non-Finnish)	0.000304%	328,663

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.Ser33=
Coding: c.99G>C
MANE Select: NM_014417
Type: single nucleotide variant
Location: chr19:47228333 (GRCh38)
Gene constraint: LOEUF 1.293 · pLI 0.05 (gnomAD)
Structure: AlphaFold pLDDT 47.60 · 13 PDB
Residue 33: 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-ser33 (accessed [today's date]).

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