Is BBS7 p.Lys681Ile (c.2042A>T) pathogenic?

BBS7 p.Lys681Ile (c.2042A>T) is classified Uncertain significance in BBS7 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-11-07). AlphaMissense: likely pathogenic (0.6393); Very rare (popmax 0.00991%, sas); Associated with Bardet-Biedl syndrome 7.

What condition is associated with BBS7 p.Lys681Ile (c.2042A>T)?

BBS7 p.Lys681Ile (c.2042A>T) is associated with Bardet-Biedl syndrome 7, Bardet-Biedl syndrome (ClinVar).

How common is BBS7 p.Lys681Ile (c.2042A>T) in the general population?

BBS7 p.Lys681Ile (c.2042A>T) is very rare (popmax 0.00991%, 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.Lys681Ile (c.2042A>T)?

AlphaMissense predicts likely pathogenic (score 0.6393) — an in-silico prediction, not a clinical call.

BBS7 p.Lys681Ile

c.2042A>T · rs534408910 · VCV1361921

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6393 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00991%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Bardet-Biedl syndrome 7

Computational evidence

Protein change
AlphaMissense	0.6393	likely pathogenic
REVEL	0.743	pathogenic-leaning
SaProt	LLR -10.86	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 7.8	GERP 1.8, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 44 kb · p 0.00015 · regional, not allelic
Overall
CADD	24.9	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 0.00991% South Asian · 9/90,832 alleles

Filtering AF 0.00515% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00376%

Overall 0.00081% 13/1,605,116 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00991%	10,092
Remaining individualsnot grpmax-eligible	0.00643%	15,550

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.Lys681Ile
Coding: c.2042A>T
MANE Select: NM_176824
dbSNP: rs534408910
Type: single nucleotide variant
Location: chr4:121825966 (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 7 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Bardet-Biedl syndrome

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.Lys681Thr 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-lys681ile (accessed [today's date]).

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