Is BBS7 p.Cys540Arg (c.1618T>C) pathogenic?

BBS7 p.Cys540Arg (c.1618T>C) is classified Uncertain significance in BBS7 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-07-26). AlphaMissense: likely benign (0.0931); Very rare (popmax 0.00223%, eas); Associated with BBS7-related disorder.

What condition is associated with BBS7 p.Cys540Arg (c.1618T>C)?

BBS7 p.Cys540Arg (c.1618T>C) is associated with BBS7-related disorder (ClinVar).

How common is BBS7 p.Cys540Arg (c.1618T>C) in the general population?

BBS7 p.Cys540Arg (c.1618T>C) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about BBS7 p.Cys540Arg (c.1618T>C)?

AlphaMissense predicts likely benign (score 0.0931) — an in-silico prediction, not a clinical call.

BBS7 p.Cys540Arg

c.1618T>C · VCV3353651

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0931 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

BBS7-related disorder

Computational evidence

Protein change
AlphaMissense	0.0931	likely benign
REVEL	0.27	benign-leaning
SaProt	LLR -7.57	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.3	GERP -0.67, phastCons 0.77
Regional constraint	o/e 0.87	unconstrained · MANE · 44 kb · p 0.00015 · regional, not allelic
Overall
CADD	16.82	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00223% East Asian · 1/44,848 alleles

Overall 6.84e-05% 1/1,461,704 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: BBS7
Protein: p.Cys540Arg
Coding: c.1618T>C
MANE Select: NM_176824
Type: single nucleotide variant
Location: chr4:121833289 (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

BBS7-related disorder

Similar variants

BBS7 c.529-2A>G Pathogenic/Likely pathogenic ★★ same condition
BBS7 p.His323Arg Pathogenic/Likely pathogenic ★★ ⚠ same condition
BBS7 p.Thr211Ile Pathogenic ★★ ⚠ same condition
BBS7 p.Ser395Asn Uncertain significance ★★ ⚠ same condition
BBS7 c.601+1G>A Likely pathogenic ★ same condition
BBS7 p.Ile249Asn Likely pathogenic ★ ⚠ same condition
BBS7 p.Trp313Ter Likely pathogenic ★ same condition
BBS7 p.Cys243Tyr Conflicting classifications of pathogenicity ★ ⚠ 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-cys540arg (accessed [today's date]).

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