Is BBS4 p.Ala263Thr (c.787G>A) pathogenic?

BBS4 p.Ala263Thr (c.787G>A) is classified Uncertain significance in BBS4 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-08-08). AlphaMissense: ambiguous (0.3495); Very rare (popmax 0.000137%); Associated with BBS4-related disorder.

What condition is associated with BBS4 p.Ala263Thr (c.787G>A)?

BBS4 p.Ala263Thr (c.787G>A) is associated with BBS4-related disorder (ClinVar).

How common is BBS4 p.Ala263Thr (c.787G>A) in the general population?

BBS4 p.Ala263Thr (c.787G>A) is very rare (popmax 0.000137%) (gnomAD).

What do computational predictors say about BBS4 p.Ala263Thr (c.787G>A)?

AlphaMissense predicts ambiguous (score 0.3495) — an in-silico prediction, not a clinical call.

BBS4 p.Ala263Thr

c.787G>A · VCV3345714

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3495 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000137%)

Conditions

BBS4-related disorder

Computational evidence

Protein change
AlphaMissense	0.3495	ambiguous
REVEL	0.583	indeterminate
SaProt	LLR -11.54	damaging
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.21 · evaluated, not missing
Constraint at this position
Conservation	phyloP 10	GERP 1.7, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 51 kb · p 0.035 · regional, not allelic
Overall
CADD	27.8	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 0.000137%

Overall 0.000137% 2/1,461,892 alleles · very rare

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: BBS4
Protein: p.Ala263Thr
Coding: c.787G>A
MANE Select: NM_033028
Type: single nucleotide variant
Location: chr15:72731380 (GRCh38)
Gene constraint: LOEUF 0.953 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.36 · 1 PDB
Residue 263: the 'interaction with pcm1' region

Full BBS4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

BBS4-related disorder

Similar variants

BBS4 p.Ala263= Likely benign ★ same residue
BBS4 c.1248+2T>C Pathogenic/Likely pathogenic ★★ same condition
BBS4 c.157-3C>G Pathogenic ★★ same condition
BBS4 c.220+1G>C Pathogenic ★★ same condition
BBS4 c.24+1G>A Likely pathogenic ★★ same condition
BBS4 c.332+8T>C Pathogenic/Likely pathogenic ★★ same condition
BBS4 c.712-1G>A Pathogenic/Likely pathogenic ★★ same condition
BBS4 p.Arg295Ter Pathogenic/Likely pathogenic ★★ same condition

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/bbs4-p-ala263thr (accessed [today's date]).

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