Is BBS4 p.Trp37Ter (c.110G>A) pathogenic?

BBS4 p.Trp37Ter (c.110G>A) is classified Likely pathogenic in BBS4 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2023-11-16). Very rare (popmax 0.00017%, nfe); Associated with BBS4-related disorder.

What condition is associated with BBS4 p.Trp37Ter (c.110G>A)?

BBS4 p.Trp37Ter (c.110G>A) is associated with BBS4-related disorder (ClinVar).

How common is BBS4 p.Trp37Ter (c.110G>A) in the general population?

BBS4 p.Trp37Ter (c.110G>A) is very rare (popmax 0.00017%, nfe) (gnomAD).

BBS4 p.Trp37Ter

c.110G>A · rs370049399 · VCV3033438

Likely pathogenic No assertion criteria

Classification

Likely pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Conditions

BBS4-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 3 of 16
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.2, phastCons 1
Overall
CADD	43.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00017% European (non-Finnish) · 2/1,179,792 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000186% 3/1,613,578 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00157%	63,888
European (non-Finnish)grpmax	0.00017%	589,897

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Trp37Ter
Coding: c.110G>A
MANE Select: NM_033028
dbSNP: rs370049399
Type: single nucleotide variant
Location: chr15:72709733 (GRCh38)
Gene constraint: LOEUF 0.953 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.36 · 1 PDB
Residue 37: the 'required for localization to centrosomes' region

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

Disease context

BBS4-related disorder

Similar variants

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
BBS4 p.Gln35Ter 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-trp37ter (accessed [today's date]).

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