Is BBS2 p.Phe112Leu (c.334T>C) pathogenic?

BBS2 p.Phe112Leu (c.334T>C) is classified Conflicting classifications of pathogenicity in BBS2 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2024-09-22). AlphaMissense: likely pathogenic (0.9643); Very rare (popmax 0.000678%, nfe); Associated with BBS2-related disorder.

What condition is associated with BBS2 p.Phe112Leu (c.334T>C)?

BBS2 p.Phe112Leu (c.334T>C) is associated with BBS2-related disorder, Bardet-Biedl syndrome 2, retinitis pigmentosa 74 (ClinVar).

How common is BBS2 p.Phe112Leu (c.334T>C) in the general population?

BBS2 p.Phe112Leu (c.334T>C) is very rare (popmax 0.000678%, nfe) (gnomAD).

What do computational predictors say about BBS2 p.Phe112Leu (c.334T>C)?

AlphaMissense predicts likely pathogenic (score 0.9643) — an in-silico prediction, not a clinical call.

BBS2 p.Phe112Leu

c.334T>C · rs772864503 · VCV554915

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.9643 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000678%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

BBS2-related disorder

Computational evidence

Protein change
AlphaMissense	0.9643	likely pathogenic · top 7% in BBS2
REVEL	0.959	strongly pathogenic-leaning
SaProt	LLR -13.36	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 1.7, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 35 kb · p 9.6e-05 · regional, not allelic
Overall
CADD	27.4	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 0.000678% European (non-Finnish) · 8/1,179,916 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000496% 8/1,613,964 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.Phe112Leu
Coding: c.334T>C
MANE Select: NM_031885
dbSNP: rs772864503
Type: single nucleotide variant
Location: chr16:56514464 (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

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

Similar variants

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
BBS2 c.1398-2A>G 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-phe112leu (accessed [today's date]).

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