Is BBS2 p.Pro134Arg (c.401C>G) pathogenic?

BBS2 p.Pro134Arg (c.401C>G) is classified Pathogenic/Likely pathogenic in BBS2 (ClinVar, Multiple submitters, 10 submitters; last evaluated 2026-05-22). AlphaMissense: likely benign (0.1516); Ultra-rare (popmax 0.0164%, mid); Associated with BBS2-related ciliopathy.

What condition is associated with BBS2 p.Pro134Arg (c.401C>G)?

BBS2 p.Pro134Arg (c.401C>G) is associated with BBS2-related ciliopathy, Bardet-Biedl syndrome 2, retinitis pigmentosa 74 (ClinVar).

How common is BBS2 p.Pro134Arg (c.401C>G) in the general population?

BBS2 p.Pro134Arg (c.401C>G) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about BBS2 p.Pro134Arg (c.401C>G)?

AlphaMissense predicts likely benign (score 0.1516) — an in-silico prediction, not a clinical call.

BBS2 p.Pro134Arg

c.401C>G · rs376306240 · VCV209043

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

AlphaMissense

likely benign

0.1516 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

BBS2-related ciliopathy

Computational evidence

Protein change
AlphaMissense	0.1516	likely benign ⚠ discordant with ClinVar
REVEL	0.933	strongly pathogenic-leaning
SaProt	LLR -10.94	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	GERP 1.9, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 35 kb · p 9.6e-05 · regional, not allelic
Overall
CADD	25.4	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 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.00153% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0013%

Overall 0.00211% 34/1,613,882 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
Admixed American	0.005%	19,997
Remaining individualsnot grpmax-eligible	0.0048%	20,822
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,598
European (non-Finnish)	0.0022%	45,382

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: BBS2
Protein: p.Pro134Arg
Coding: c.401C>G
MANE Select: NM_031885
dbSNP: rs376306240
Type: single nucleotide variant
Location: chr16:56511229 (GRCh38)
Gene constraint: LOEUF 0.892 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.49
Residue 134: a UniProt-annotated variant site (in rp74)

Full BBS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Also linked: Bardet-Biedl syndrome 2 retinitis pigmentosa 74 Bardet-Biedl syndrome retinitis pigmentosa

Similar variants

BBS2 p.Pro134Ser Uncertain significance ★ ⚠ same residue
BBS2 c.118-1G>T Likely pathogenic ★★ same condition
BBS2 c.118-2A>C Likely pathogenic ★★ same condition
BBS2 c.118-2A>G Likely pathogenic ★★ same condition
BBS2 c.1225+2T>C Likely pathogenic ★★ same condition
BBS2 c.1225+2T>G Likely pathogenic ★★ same condition
BBS2 c.1397+1G>A Pathogenic/Likely pathogenic ★★ same condition
BBS2 c.1397+2T>C 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/bbs2-p-pro134arg (accessed [today's date]).

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