Is BBS2 p.Phe217Val (c.649T>G) pathogenic?

BBS2 p.Phe217Val (c.649T>G) is classified Uncertain significance in BBS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-06). AlphaMissense: likely pathogenic (0.8503); Very rare (popmax 8.48e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with BBS2 p.Phe217Val (c.649T>G)?

BBS2 p.Phe217Val (c.649T>G) is associated with Inborn genetic diseases (ClinVar).

How common is BBS2 p.Phe217Val (c.649T>G) in the general population?

BBS2 p.Phe217Val (c.649T>G) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about BBS2 p.Phe217Val (c.649T>G)?

AlphaMissense predicts likely pathogenic (score 0.8503) — an in-silico prediction, not a clinical call.

BBS2 p.Phe217Val

c.649T>G · rs2543721405 · VCV2533893

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8503 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8503	likely pathogenic
REVEL	0.917	moderately pathogenic-leaning
SaProt	LLR -11.73	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 9.4	GERP 1.9, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 35 kb · p 9.6e-05 · regional, not allelic
Overall
CADD	27.3	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 8.48e-05% European (non-Finnish) · 1/1,179,142 alleles

Overall 6.85e-05% 1/1,460,518 alleles · very rare

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.Phe217Val
Coding: c.649T>G
MANE Select: NM_031885
dbSNP: rs2543721405
Type: single nucleotide variant
Location: chr16:56506188 (GRCh38)
Gene constraint: LOEUF 0.892 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.49

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

BBS2 p.Phe217Cys Likely pathogenic ★ same residue
BBS2 p.Phe217Leu Uncertain significance ★ ⚠ same residue
BBS2 p.Ala682Thr Uncertain significance ★★ ⚠ same condition
BBS2 p.Arg353Cys Uncertain significance ★★ ⚠ same condition
BBS2 p.Arg374Gln Uncertain significance ★★ ⚠ same condition
BBS2 p.Arg539Gln Uncertain significance ★★ ⚠ same condition
BBS2 p.Arg622Gln Uncertain significance ★★ ⚠ same condition
BBS2 p.Arg661His Uncertain significance ★★ ⚠ 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-phe217val (accessed [today's date]).

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