Is BBS7 p.Asp421Glu (c.1263T>A) pathogenic?

BBS7 p.Asp421Glu (c.1263T>A) is classified Conflicting classifications of pathogenicity in BBS7 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-10-05). AlphaMissense: likely benign (0.1141); Ultra-rare (popmax 0.0488%, nfe); Associated with Bardet-Biedl syndrome 7.

What condition is associated with BBS7 p.Asp421Glu (c.1263T>A)?

BBS7 p.Asp421Glu (c.1263T>A) is associated with Bardet-Biedl syndrome 7, Bardet-Biedl syndrome (ClinVar).

How common is BBS7 p.Asp421Glu (c.1263T>A) in the general population?

BBS7 p.Asp421Glu (c.1263T>A) is ultra-rare (popmax 0.0488%, nfe) (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.Asp421Glu (c.1263T>A)?

AlphaMissense predicts likely benign (score 0.1141) — an in-silico prediction, not a clinical call.

BBS7 p.Asp421Glu

c.1263T>A · rs146412602 · VCV838538

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.1141 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0488%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Bardet-Biedl syndrome 7

Computational evidence

Protein change
AlphaMissense	0.1141	likely benign
REVEL	0.217	benign-leaning
SaProt	LLR -3.78	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 2.5	GERP -0.68, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 44 kb · p 0.00015 · regional, not allelic
Overall
CADD	14.67	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 0.0488% European (non-Finnish) · 572/1,172,794 alleles

Filtering AF 0.0454% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0441%

Overall 0.0392% 629/1,602,722 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0488%	2,050
Remaining individualsnot grpmax-eligible	0.0371%	2,693
Admixed American	0.0219%	4,556
Finnishnot grpmax-eligible	0.0173%	5,767
African / African-American	0.0134%	7,480

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.Asp421Glu
Coding: c.1263T>A
MANE Select: NM_176824
dbSNP: rs146412602
Type: single nucleotide variant
Location: chr4:121843969 (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.Asp421= Likely benign ★ same residue
BBS7 p.Asp421Asn 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

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-asp421glu (accessed [today's date]).

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