Is BBS4 p.Arg22Trp (c.64C>T) pathogenic?

BBS4 p.Arg22Trp (c.64C>T) is classified Conflicting classifications of pathogenicity in BBS4 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2024-03-19). AlphaMissense: likely benign (0.1579); Ultra-rare (popmax 0.0634%, amr); Associated with Bardet-Biedl syndrome.

What condition is associated with BBS4 p.Arg22Trp (c.64C>T)?

BBS4 p.Arg22Trp (c.64C>T) is associated with Bardet-Biedl syndrome, Bardet-Biedl syndrome 4 (ClinVar).

How common is BBS4 p.Arg22Trp (c.64C>T) in the general population?

BBS4 p.Arg22Trp (c.64C>T) is ultra-rare (popmax 0.0634%, amr) (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.Arg22Trp (c.64C>T)?

AlphaMissense predicts likely benign (score 0.1579) — an in-silico prediction, not a clinical call.

BBS4 p.Arg22Trp

c.64C>T · rs727503820 · VCV166732

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.1579 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0634%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Bardet-Biedl syndrome

Computational evidence

Protein change
AlphaMissense	0.1579	likely benign
REVEL	0.089	moderately benign-leaning
SaProt	LLR -8.71	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.23 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.88	GERP -0.63
Regional constraint	o/e 1.09	unconstrained · MANE · 51 kb · p 0.035 · regional, not allelic
Overall
CADD	17.36	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 0.0634% Admixed American · 38/59,896 alleles

Filtering AF 0.0475% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.042%

Overall 0.00767% 123/1,602,946 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0634%	1,576
South Asian	0.0121%	8,249
African / African-American	0.0121%	8,288
Remaining individualsnot grpmax-eligible	0.0113%	8,872
European (non-Finnish)	0.0047%	21,283
East Asian	0.00447%	22,389
Finnishnot grpmax-eligible	0.00157%	63,884

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.Arg22Trp
Coding: c.64C>T
MANE Select: NM_033028
dbSNP: rs727503820
Type: single nucleotide variant
Location: chr15:72695216 (GRCh38)
Gene constraint: LOEUF 0.953 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.36 · 1 PDB
Residue 22: the 'required for localization to centrosomes' region; the 'disordered' 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

Also linked: Bardet-Biedl syndrome 4

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.Arg22Gln Uncertain significance ★★ ⚠ same residue
BBS4 p.Arg22= Likely benign ★ same residue
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

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-arg22trp (accessed [today's date]).

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