Is BBS12 p.Val273Ala (c.818T>C) pathogenic?

BBS12 p.Val273Ala (c.818T>C) is classified Uncertain significance in BBS12 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-01). AlphaMissense: likely benign (0.0803); Very rare (popmax 0.00333%, amr).

How common is BBS12 p.Val273Ala (c.818T>C) in the general population?

BBS12 p.Val273Ala (c.818T>C) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about BBS12 p.Val273Ala (c.818T>C)?

AlphaMissense predicts likely benign (score 0.0803) — an in-silico prediction, not a clinical call.

BBS12 p.Val273Ala

c.818T>C · VCV4084329

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0803 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0803	likely benign
REVEL	0.106	moderately benign-leaning
SaProt	LLR -1.31	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 -1.8	GERP -3.8
Regional constraint	o/e 0.90	unconstrained · MANE · 2,129 bp · p 0.0042 · regional, not allelic
Overall
CADD	7.123	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 0.00333% Admixed American · 2/60,024 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000547% 8/1,461,880 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	30,012
Remaining individualsnot grpmax-eligible	0.0016%	62,512
European (non-Finnish)	0.000424%	236,007

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: BBS12
Protein: p.Val273Ala
Coding: c.818T>C
MANE Select: NM_152618
Type: single nucleotide variant
Location: chr4:122742710 (GRCh38)
Gene constraint: LOEUF 1.419 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.92

Full BBS12 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BBS12 p.Val273Ile Uncertain significance ⚠ same residue
BBS12 p.Ala289Pro Likely pathogenic ★★ same type
BBS12 p.Arg214Ter Pathogenic/Likely pathogenic ★★ same type
BBS12 p.Arg355Ter Pathogenic ★★ same type
BBS12 p.Arg675Ter Pathogenic/Likely pathogenic ★★ same type
BBS12 p.Gln149Ter Pathogenic/Likely pathogenic ★★ same type
BBS12 p.Gln228Ter Pathogenic/Likely pathogenic ★★ same type
BBS12 p.Gln300Ter 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/bbs12-p-val273ala (accessed [today's date]).

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