Is BBS4 p.Cys264Phe (c.791G>T) pathogenic?

BBS4 p.Cys264Phe (c.791G>T) is classified Likely pathogenic in BBS4 (ClinVar, No assertion criteria, 2 submitters; last evaluated 2019-09-26). AlphaMissense: likely benign (0.0927); Common (popmax 5.75%, amr) — too common for a highly-penetrant pathogenic allele; Associated with Bardet-Biedl syndrome 4.

What condition is associated with BBS4 p.Cys264Phe (c.791G>T)?

BBS4 p.Cys264Phe (c.791G>T) is associated with Bardet-Biedl syndrome 4 (ClinVar).

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.Cys264Phe (c.791G>T)?

AlphaMissense predicts likely benign (score 0.0927) — an in-silico prediction, not a clinical call.

BBS4 p.Cys264Phe

Q: How common is BBS4 p.Cys264Phe (c.791G>T) in the general population?

BBS4 p.Cys264Phe (c.791G>T) is common (popmax 5.75%, amr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.791G>T · rs200113494 · VCV800967

Likely pathogenic No assertion criteria

Classification

Likely pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0927 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 5.75%, amr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Bardet-Biedl syndrome 4

Computational evidence

Protein change
AlphaMissense	0.0927	likely benign ⚠ discordant with ClinVar
REVEL	0.318	indeterminate
SaProt	LLR -7.07	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.5	GERP 0.76, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 51 kb · p 0.035 · regional, not allelic
Overall
CADD	17.05	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 5.75% Admixed American · 3,257/56,670 alleles

Filtering AF 5.58% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.52%

Overall 0.985% 15,473/1,570,836 alleles · common

Ancestry group	Frequency	1 in
Admixed Americangrpmax	5.75%	17
East Asian	3.41%	29
Finnishnot grpmax-eligible	2.95%	34
Middle Eastern	2.1%	48
South Asian	1.79%	56
Ashkenazi Jewishnot grpmax-eligible	1.2%	83
African / African-American	0.964%	104
Remaining individualsnot grpmax-eligible	0.719%	139
European (non-Finnish)	0.516%	194

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.Cys264Phe
Coding: c.791G>T
MANE Select: NM_033028
dbSNP: rs200113494
Type: single nucleotide variant
Location: chr15:72731384 (GRCh38)
Gene constraint: LOEUF 0.953 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.36 · 1 PDB
Residue 264: the 'interaction with pcm1' region

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

Disease context

Bardet-Biedl syndrome 4 — 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 p.Cys264Tyr Uncertain significance ⚠ same residue
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.24+1G>A Likely pathogenic ★★ same condition
BBS4 c.24+1G>T 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-cys264phe (accessed [today's date]).

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