Is BBS4 p.Leu113Phe (c.337C>T) pathogenic?

BBS4 p.Leu113Phe (c.337C>T) is classified Uncertain significance in BBS4 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2024-10-22). AlphaMissense: likely pathogenic (0.8776); Ultra-rare (popmax 0.044%, nfe); Associated with Bardet-Biedl syndrome.

What condition is associated with BBS4 p.Leu113Phe (c.337C>T)?

BBS4 p.Leu113Phe (c.337C>T) is associated with Bardet-Biedl syndrome (ClinVar).

How common is BBS4 p.Leu113Phe (c.337C>T) in the general population?

BBS4 p.Leu113Phe (c.337C>T) is ultra-rare (popmax 0.044%, nfe) (gnomAD).

How is Bardet-Biedl syndrome inherited?

Typically Autosomal recessive, Oligogenic (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about BBS4 p.Leu113Phe (c.337C>T)?

AlphaMissense predicts likely pathogenic (score 0.8776) — an in-silico prediction, not a clinical call.

BBS4 p.Leu113Phe

c.337C>T · rs760909426 · VCV846825

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.8776 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.044%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Bardet-Biedl syndrome

Computational evidence

Protein change
AlphaMissense	0.8776	likely pathogenic
REVEL	0.319	indeterminate
SaProt	LLR -5.66	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.6, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 51 kb · p 0.035 · regional, not allelic
Overall
CADD	27.7	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 0.044% European (non-Finnish) · 517/1,174,166 alleles

Filtering AF 0.0409% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0396%

Overall 0.0363% 582/1,604,726 alleles · ultra-rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0471%	2,123
Remaining individualsnot grpmax-eligible	0.0451%	2,218
European (non-Finnish)grpmax	0.044%	2,271
African / African-American	0.00936%	10,679

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.Leu113Phe
Coding: c.337C>T
MANE Select: NM_033028
dbSNP: rs760909426
Type: single nucleotide variant
Location: chr15:72716782 (GRCh38)
Gene constraint: LOEUF 0.953 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.36 · 1 PDB
Residue 113: the 'interaction with pcm1' region

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

Disease context

Bardet-Biedl syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Bardet-Biedl syndrome (Orphanet):

Inheritance: Autosomal recessive, Oligogenic
Onset: Antenatal, Childhood, Infancy, Neonatal
Prevalence: 1-9 / 100 000 (Specific population)

Similar variants

BBS4 c.1106+2T>A Pathogenic/Likely pathogenic ★★ same condition
BBS4 c.1248+1G>A Pathogenic/Likely pathogenic ★★ same condition
BBS4 c.1248+1G>T Pathogenic ★★ same condition
BBS4 c.1248+2T>C Pathogenic/Likely pathogenic ★★ same condition
BBS4 c.1249-2A>C Likely pathogenic ★★ same condition
BBS4 c.157-2A>G Pathogenic ★★ same condition
BBS4 c.157-3C>G Pathogenic ★★ same condition
BBS4 c.220+1G>C 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-leu113phe (accessed [today's date]).

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