Is BBX p.Thr348Ser (c.1043C>G) pathogenic?

BBX p.Thr348Ser (c.1043C>G) is classified Uncertain significance in BBX (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-27). AlphaMissense: likely benign (0.0853); Very rare (popmax 0.00178%, nfe).

How common is BBX p.Thr348Ser (c.1043C>G) in the general population?

BBX p.Thr348Ser (c.1043C>G) is very rare (popmax 0.00178%, nfe) (gnomAD).

What do computational predictors say about BBX p.Thr348Ser (c.1043C>G)?

AlphaMissense predicts likely benign (score 0.0853) — an in-silico prediction, not a clinical call.

BBX p.Thr348Ser

c.1043C>G · rs748639341 · VCV2368617

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0853 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00178%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0853	likely benign
REVEL	0.253	benign-leaning
SaProt	LLR -6.00	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.24	gain · loss 0.00 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 0.13	GERP -1.7, phastCons 0.014
Regional constraint	o/e 0.99	unconstrained · MANE · 889 bp · p 0.78 · regional, not allelic
Overall
CADD	6.164	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 0.00178% European (non-Finnish) · 21/1,179,722 alleles

Filtering AF 0.00114% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000971%

Overall 0.00136% 22/1,612,924 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00178%	56,177
Remaining individualsnot grpmax-eligible	0.0016%	62,456

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: BBX
Protein: p.Thr348Ser
Coding: c.1043C>G
MANE Select: NM_001142568
dbSNP: rs748639341
Type: single nucleotide variant
Location: chr3:107772764 (GRCh38)
Gene constraint: LOEUF 0.359 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 50.79

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

Similar variants

BBX p.Ala442Thr Benign ★★ same type
BBX p.Ala60= Likely benign ★★ same type
BBX p.Ala892= Benign ★★ same type
BBX p.Ala139Thr Uncertain significance ★ ⚠ same type
BBX p.Ala143Gly Uncertain significance ★ ⚠ same type
BBX p.Ala269Pro Uncertain significance ★ ⚠ same type
BBX p.Ala354Thr Uncertain significance ★ ⚠ same type
BBX p.Ala375Thr 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/bbx-p-thr348ser (accessed [today's date]).

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