Is BBOX1 p.Leu320His (c.959T>A) pathogenic?

BBOX1 p.Leu320His (c.959T>A) is classified Uncertain significance in BBOX1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-26). AlphaMissense: likely benign (0.2044); Ultra-rare (popmax 0.0134%, amr).

How common is BBOX1 p.Leu320His (c.959T>A) in the general population?

BBOX1 p.Leu320His (c.959T>A) is ultra-rare (popmax 0.0134%, amr) (gnomAD).

What do computational predictors say about BBOX1 p.Leu320His (c.959T>A)?

AlphaMissense predicts likely benign (score 0.2044) — an in-silico prediction, not a clinical call.

BBOX1 p.Leu320His

c.959T>A · VCV3821857

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2044 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0134%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2044	likely benign
REVEL	0.776	moderately pathogenic-leaning
SaProt	LLR -11.24	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 72 kb · p 0.9 · regional, not allelic
Overall
CADD	25.9	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 0.0134% Admixed American · 8/59,800 alleles

Filtering AF 0.00663% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00484%

Overall 0.0036% 58/1,613,182 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0134%	7,475
European (non-Finnish)	0.00407%	24,579
Remaining individualsnot grpmax-eligible	0.0016%	62,456
South Asian	0.0011%	90,812

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.Leu320His
Coding: c.959T>A
MANE Select: NM_003986
Type: single nucleotide variant
Location: chr11:27125776 (GRCh38)
Gene constraint: LOEUF 0.983 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.06 · 12 PDB
Residue 320: an α-helix

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

Similar variants

BBOX1 p.Leu320Arg Uncertain significance ★ ⚠ same residue
BBOX1 p.Leu320= Likely benign same residue
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

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-leu320his (accessed [today's date]).

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