Is BBOX1 p.Thr203Ser (c.608C>G) pathogenic?

BBOX1 p.Thr203Ser (c.608C>G) is classified Uncertain significance in BBOX1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-18). AlphaMissense: likely benign (0.2701); Very rare (popmax 0.00268%, afr).

How common is BBOX1 p.Thr203Ser (c.608C>G) in the general population?

BBOX1 p.Thr203Ser (c.608C>G) is very rare (popmax 0.00268%, afr) (gnomAD).

What do computational predictors say about BBOX1 p.Thr203Ser (c.608C>G)?

AlphaMissense predicts likely benign (score 0.2701) — an in-silico prediction, not a clinical call.

BBOX1 p.Thr203Ser

c.608C>G · VCV4645313

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2701 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00268%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2701	likely benign
REVEL	0.774	moderately pathogenic-leaning
SaProt	LLR -9.56	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.7, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 72 kb · p 0.9 · regional, not allelic
Overall
CADD	26.5	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 0.00268% African / African-American · 2/74,656 alleles

Filtering AF 0.000616% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000474%

Overall 0.000993% 16/1,610,914 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00268%	37,328
Remaining individualsnot grpmax-eligible	0.0016%	62,312
European (non-Finnish)	0.0011%	90,624

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: BBOX1
Protein: p.Thr203Ser
Coding: c.608C>G
MANE Select: NM_003986
Type: single nucleotide variant
Location: chr11:27115526 (GRCh38)
Gene constraint: LOEUF 0.983 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.06 · 12 PDB

Full BBOX1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BBOX1 p.Ala207= Benign ★★ same type
BBOX1 p.Phe310= Benign ★★ same type
BBOX1 p.Tyr133= Benign ★★ same type
BBOX1 p.Ala14Asp Uncertain significance ★ ⚠ same type
BBOX1 p.Ala155Thr Uncertain significance ★ ⚠ same type
BBOX1 p.Ala193Ser Uncertain significance ★ ⚠ same type
BBOX1 p.Ala248Val Uncertain significance ★ ⚠ same type
BBOX1 p.Ala354Thr 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/bbox1-p-thr203ser (accessed [today's date]).

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