Is BBS9 p.Val461Met (c.1381G>A) pathogenic?

BBS9 p.Val461Met (c.1381G>A) is classified Uncertain significance in BBS9 (ClinVar, Single submitter, 2 submitters; last evaluated 2018-09-25). AlphaMissense: likely benign (0.3268); Ultra-rare (popmax 0.0165%, mid).

How common is BBS9 p.Val461Met (c.1381G>A) in the general population?

BBS9 p.Val461Met (c.1381G>A) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about BBS9 p.Val461Met (c.1381G>A)?

AlphaMissense predicts likely benign (score 0.3268) — an in-silico prediction, not a clinical call.

BBS9 p.Val461Met

c.1381G>A · VCV3356139

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.3268 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.3268	likely benign
REVEL	0.197	benign-leaning
SaProt	LLR -10.40	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.5	GERP 1.8, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 459 kb · p 0.062 · regional, not allelic
Overall
CADD	25.4	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 0.0165% Middle Eastern · 1/6,078 alleles

Filtering AF 0.00074% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000277%

Overall 0.000496% 8/1,613,322 alleles · ultra-rare exomes 8/1,461,158 · genomes 0/152,164 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,078
East Asian	0.00446%	22,400
Remaining individualsnot grpmax-eligible	0.0032%	31,229
African / African-American	0.00267%	37,445
European (non-Finnish)	8.48e-05%	1,179,586

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: BBS9
Protein: p.Val461Met
Coding: c.1381G>A
MANE Select: NM_198428
Type: single nucleotide variant
Location: chr7:33349119 (GRCh38)
Gene constraint: LOEUF 0.959 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.41 · 2 PDB

Full BBS9 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BBS9 p.Val461Leu Uncertain significance ★ ⚠ same residue
BBS9 c.1329+1738C>T Likely pathogenic ★★ same type
BBS9 c.1552+2T>A Likely pathogenic ★★ same type
BBS9 c.1693+1G>A Pathogenic/Likely pathogenic ★★ same type
BBS9 c.1789+1G>A Pathogenic/Likely pathogenic ★★ same type
BBS9 c.1789+1G>C Pathogenic/Likely pathogenic ★★ same type
BBS9 c.2299-2A>C Likely pathogenic ★★ same type
BBS9 c.2521+1G>T Likely pathogenic ★★ same type

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/bbs9-p-val461met (accessed [today's date]).

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