Is BBS5 p.Ser224Arg (c.670A>C) pathogenic?

BBS5 p.Ser224Arg (c.670A>C) is classified Uncertain significance in BBS5 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-05). AlphaMissense: likely pathogenic (0.9985); Very rare (popmax 0.00667%, amr); Associated with Bardet-Biedl syndrome.

What condition is associated with BBS5 p.Ser224Arg (c.670A>C)?

BBS5 p.Ser224Arg (c.670A>C) is associated with Bardet-Biedl syndrome (ClinVar).

How common is BBS5 p.Ser224Arg (c.670A>C) in the general population?

BBS5 p.Ser224Arg (c.670A>C) is very rare (popmax 0.00667%, 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.Ser224Arg (c.670A>C)?

AlphaMissense predicts likely pathogenic (score 0.9985) — an in-silico prediction, not a clinical call.

BBS5 p.Ser224Arg

c.670A>C · rs760706516 · VCV2193342

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9985 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Bardet-Biedl syndrome

Computational evidence

Protein change
AlphaMissense	0.9985	likely pathogenic · top 2% in BBS5
REVEL	0.714	pathogenic-leaning
SaProt	LLR -15.79	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 25 kb · p 0.023 · regional, not allelic
Overall
CADD	26.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00667% Admixed American · 4/59,926 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.000378% 6/1,588,336 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00667%	14,981
European (non-Finnish)	0.000173%	578,613

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.Ser224Arg
Coding: c.670A>C
MANE Select: NM_152384
dbSNP: rs760706516
Type: single nucleotide variant
Location: chr2:169497678 (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

For Bardet-Biedl syndrome (Orphanet):

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

Similar variants

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
BBS5 p.Arg89Ter 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-ser224arg (accessed [today's date]).

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