Is BBS5 p.Arg66Lys (c.197G>A) pathogenic?

BBS5 p.Arg66Lys (c.197G>A) is classified Uncertain significance in BBS5 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-01-13). AlphaMissense: likely benign (0.264); Ultra-rare (popmax 0.08%, amr); Associated with Bardet-Biedl syndrome.

What condition is associated with BBS5 p.Arg66Lys (c.197G>A)?

BBS5 p.Arg66Lys (c.197G>A) is associated with Bardet-Biedl syndrome, Bardet-Biedl syndrome 5 (ClinVar).

How common is BBS5 p.Arg66Lys (c.197G>A) in the general population?

BBS5 p.Arg66Lys (c.197G>A) is ultra-rare (popmax 0.08%, 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 BBS5 p.Arg66Lys (c.197G>A)?

AlphaMissense predicts likely benign (score 0.264) — an in-silico prediction, not a clinical call.

BBS5 p.Arg66Lys

c.197G>A · rs200250398 · VCV1381795

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.264 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.08%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Bardet-Biedl syndrome

Computational evidence

Protein change
AlphaMissense	0.264	likely benign
REVEL	0.494	indeterminate
SaProt	LLR -5.97	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	Δ0.39	donor loss · deltas
Pangolin	Δ0.26	loss · gain 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 12	GERP 1.6, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 25 kb · p 0.023 · regional, not allelic
Overall
CADD	25.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.08% Admixed American · 48/60,010 alleles

Filtering AF 0.0619% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0555%

Overall 0.00304% 49/1,609,856 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.08%	1,250
South Asian	0.0011%	90,974

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: BBS5
Protein: p.Arg66Lys
Coding: c.197G>A
MANE Select: NM_152384
dbSNP: rs200250398
Type: single nucleotide variant
Location: chr2:169487123 (GRCh38)
Gene constraint: LOEUF 0.884 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 88.87 · 1 PDB

Full BBS5 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 5

For Bardet-Biedl syndrome (Orphanet):

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

Similar variants

BBS5 p.Arg66Gly Uncertain significance ⚠ same residue
BBS5 c.143-1G>C Pathogenic/Likely pathogenic ★★ same condition
BBS5 c.209-1G>A Pathogenic/Likely pathogenic ★★ same condition
BBS5 c.209-2A>G Likely pathogenic ★★ same condition
BBS5 c.522+3A>G Pathogenic/Likely pathogenic ★★ same condition
BBS5 c.681+1G>T Pathogenic/Likely pathogenic ★★ same condition
BBS5 p.Arg138Cys Likely pathogenic ★★ same condition
BBS5 p.Arg138His 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/bbs5-p-arg66lys (accessed [today's date]).

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