Is BBS7 p.Arg446Gln (c.1337G>A) pathogenic?

BBS7 p.Arg446Gln (c.1337G>A) is classified Conflicting classifications of pathogenicity in BBS7 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-01-18). AlphaMissense: likely pathogenic (0.7552); Rare (popmax 0.357%, sas); Associated with Bardet-Biedl syndrome.

What condition is associated with BBS7 p.Arg446Gln (c.1337G>A)?

BBS7 p.Arg446Gln (c.1337G>A) is associated with Bardet-Biedl syndrome, Bardet-Biedl syndrome 7 (ClinVar).

How common is BBS7 p.Arg446Gln (c.1337G>A) in the general population?

BBS7 p.Arg446Gln (c.1337G>A) is rare (popmax 0.357%, sas) (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 BBS7 p.Arg446Gln (c.1337G>A)?

AlphaMissense predicts likely pathogenic (score 0.7552) — an in-silico prediction, not a clinical call.

BBS7 p.Arg446Gln

c.1337G>A · rs372685495 · VCV1339330

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.7552 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.357%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Bardet-Biedl syndrome

Computational evidence

Protein change
AlphaMissense	0.7552	likely pathogenic
REVEL	0.854	moderately pathogenic-leaning
SaProt	LLR -14.18	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 7.6	GERP 1.8, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 44 kb · p 0.00015 · regional, not allelic
Overall
CADD	32.0	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 0.357% South Asian · 325/91,062 alleles

Filtering AF 0.325% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.312%

Overall 0.0216% 348/1,613,628 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.357%	280
Middle Eastern	0.0165%	6,056
Remaining individualsnot grpmax-eligible	0.0096%	10,416
African / African-American	0.00534%	18,743
East Asian	0.00223%	44,840
European (non-Finnish)	0.000932%	107,253

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: BBS7
Protein: p.Arg446Gln
Coding: c.1337G>A
MANE Select: NM_176824
dbSNP: rs372685495
Type: single nucleotide variant
Location: chr4:121839665 (GRCh38)
Gene constraint: LOEUF 0.701 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 92.99

Full BBS7 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Bardet-Biedl syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Bardet-Biedl syndrome 7

For Bardet-Biedl syndrome (Orphanet):

Inheritance: Autosomal recessive, Oligogenic
Onset: Antenatal, Childhood, Infancy, Neonatal
Prevalence: 1-9 / 100 000 (Specific population)

Similar variants

BBS7 p.Arg446Trp Uncertain significance ★★ ⚠ same residue
BBS7 c.1305+2T>A Likely pathogenic ★★ same condition
BBS7 c.1371+1G>A Likely pathogenic ★★ same condition
BBS7 c.1512-1G>A Likely pathogenic ★★ same condition
BBS7 c.1677-2A>G Pathogenic/Likely pathogenic ★★ same condition
BBS7 c.1891-2A>C Pathogenic/Likely pathogenic ★★ same condition
BBS7 c.342-2A>G Pathogenic/Likely pathogenic ★★ same condition
BBS7 c.529-2A>G Pathogenic/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/bbs7-p-arg446gln (accessed [today's date]).

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