Is BBS7 p.Phe641Leu (c.1923T>A) pathogenic?

BBS7 p.Phe641Leu (c.1923T>A) is classified Uncertain significance in BBS7 (ClinVar, Single submitter, 2 submitters; last evaluated 2021-12-15). AlphaMissense: likely pathogenic (0.9315); Very rare (popmax 0.00167%, amr); Associated with Bardet-Biedl syndrome.

What condition is associated with BBS7 p.Phe641Leu (c.1923T>A)?

BBS7 p.Phe641Leu (c.1923T>A) is associated with Bardet-Biedl syndrome (ClinVar).

How common is BBS7 p.Phe641Leu (c.1923T>A) in the general population?

BBS7 p.Phe641Leu (c.1923T>A) is very rare (popmax 0.00167%, amr) (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.Phe641Leu (c.1923T>A)?

AlphaMissense predicts likely pathogenic (score 0.9315) — an in-silico prediction, not a clinical call.

BBS7 p.Phe641Leu

c.1923T>A · rs748634596 · VCV1939765

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9315 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Bardet-Biedl syndrome

Computational evidence

Protein change
AlphaMissense	0.9315	likely pathogenic
REVEL	0.485	indeterminate
SaProt	LLR -6.11	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.7	GERP -0.66, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 44 kb · p 0.00015 · regional, not allelic
Overall
CADD	17.57	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 0.00167% Admixed American · 1/59,990 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000248% 4/1,613,700 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,990
Remaining individualsnot grpmax-eligible	0.0016%	62,464
European (non-Finnish)	0.00017%	589,918

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.Phe641Leu
Coding: c.1923T>A
MANE Select: NM_176824
dbSNP: rs748634596
Type: single nucleotide variant
Location: chr4:121828237 (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

For Bardet-Biedl syndrome (Orphanet):

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

Similar variants

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.849+1G>C Pathogenic/Likely pathogenic ★★ same condition
BBS7 p.Arg280Ter 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-phe641leu (accessed [today's date]).

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