Is BBS5 p.Phe181Ser (c.542T>C) pathogenic?

BBS5 p.Phe181Ser (c.542T>C) is classified Conflicting classifications of pathogenicity in BBS5 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2024-11-15). AlphaMissense: likely pathogenic (0.8142); Ultra-rare (popmax 0.0179%, eas); Associated with Bardet-Biedl syndrome 5.

What condition is associated with BBS5 p.Phe181Ser (c.542T>C)?

BBS5 p.Phe181Ser (c.542T>C) is associated with Bardet-Biedl syndrome 5, Bardet-Biedl syndrome (ClinVar).

How common is BBS5 p.Phe181Ser (c.542T>C) in the general population?

BBS5 p.Phe181Ser (c.542T>C) is ultra-rare (popmax 0.0179%, eas) (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.Phe181Ser (c.542T>C)?

AlphaMissense predicts likely pathogenic (score 0.8142) — an in-silico prediction, not a clinical call.

BBS5 p.Phe181Ser

c.542T>C · rs758508869 · VCV578815

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.8142 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0179%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Bardet-Biedl syndrome 5

Computational evidence

Protein change
AlphaMissense	0.8142	likely pathogenic
REVEL	0.757	pathogenic-leaning
SaProt	LLR -13.87	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 7.8	GERP 1.9, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 25 kb · p 0.023 · regional, not allelic
Overall
CADD	25.8	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 0.0179% East Asian · 8/44,794 alleles

Filtering AF 0.00885% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00642%

Overall 0.00248% 40/1,612,462 alleles · ultra-rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0352%	2,839
East Asiangrpmax	0.0179%	5,599
Admixed American	0.015%	6,668
European (non-Finnish)	8.48e-05%	1,178,575

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Phe181Ser
Coding: c.542T>C
MANE Select: NM_152384
dbSNP: rs758508869
Type: single nucleotide variant
Location: chr2:169493760 (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 5 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Bardet-Biedl syndrome

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-phe181ser (accessed [today's date]).

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