Is BBS5 p.Leu50Pro (c.149T>C) pathogenic?

BBS5 p.Leu50Pro (c.149T>C) is classified Uncertain significance in BBS5 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-08-12). AlphaMissense: likely pathogenic (0.9948); Absent from gnomAD v4.1.

How common is BBS5 p.Leu50Pro (c.149T>C) in the general population?

BBS5 p.Leu50Pro (c.149T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about BBS5 p.Leu50Pro (c.149T>C)?

AlphaMissense predicts likely pathogenic (score 0.9948) — an in-silico prediction, not a clinical call.

BBS5 p.Leu50Pro

c.149T>C · rs1683498718 · VCV1307386

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9948 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9948	likely pathogenic · top 4% in BBS5
REVEL	0.964	strongly pathogenic-leaning
SaProt	LLR -14.68	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>G here scores Δ0.20 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.8	GERP 1.6, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 25 kb · p 0.023 · regional, not allelic
Overall
CADD	32.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: BBS5
Protein: p.Leu50Pro
Coding: c.149T>C
MANE Select: NM_152384
dbSNP: rs1683498718
Type: single nucleotide variant
Location: chr2:169487075 (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

Similar variants

BBS5 p.Leu50Ile Uncertain significance ★ ⚠ same residue
BBS5 c.143-1G>C Pathogenic/Likely pathogenic ★★ same type
BBS5 c.209-1G>A Pathogenic/Likely pathogenic ★★ same type
BBS5 c.209-2A>G Likely pathogenic ★★ same type
BBS5 c.522+3A>G Pathogenic/Likely pathogenic ★★ same type
BBS5 c.681+1G>T Pathogenic/Likely pathogenic ★★ same type
BBS5 p.Arg138Cys Likely pathogenic ★★ same type
BBS5 p.Arg138His Pathogenic/Likely pathogenic ★★ same type

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-leu50pro (accessed [today's date]).

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