Is B9D2 p.Arg75Gln (c.224G>A) pathogenic?

B9D2 p.Arg75Gln (c.224G>A) is classified Conflicting classifications of pathogenicity in B9D2 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-02-01). AlphaMissense: likely benign (0.1936); Rare (popmax 0.525%, eas); Associated with ciliopathy.

What condition is associated with B9D2 p.Arg75Gln (c.224G>A)?

B9D2 p.Arg75Gln (c.224G>A) is associated with ciliopathy, Joubert syndrome, Meckel syndrome (ClinVar).

How common is B9D2 p.Arg75Gln (c.224G>A) in the general population?

B9D2 p.Arg75Gln (c.224G>A) is rare (popmax 0.525%, eas) (gnomAD).

What do computational predictors say about B9D2 p.Arg75Gln (c.224G>A)?

AlphaMissense predicts likely benign (score 0.1936) — an in-silico prediction, not a clinical call.

B9D2 p.Arg75Gln

c.224G>A · rs148087680 · VCV1970648

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1936 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.525%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ciliopathy

Computational evidence

Protein change
AlphaMissense	0.1936	likely benign
REVEL	0.177	moderately benign-leaning
SaProt	LLR -8.29	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.22 · evaluated, not missing
Constraint at this position
Conservation	phyloP 4.8	GERP 0.27, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 8,816 bp · p 0.14 · regional, not allelic
Overall
CADD	24.9	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 0.525% East Asian · 232/44,232 alleles

Filtering AF 0.469% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.448%

Overall 0.0185% 295/1,594,726 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.525%	191
Ashkenazi Jewishnot grpmax-eligible	0.0556%	1,797
Remaining individualsnot grpmax-eligible	0.013%	7,702
South Asian	0.0101%	9,914
African / African-American	0.00537%	18,621
European (non-Finnish)	0.00214%	46,743
Admixed American	0.00171%	58,312

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: B9D2
Protein: p.Arg75Gln
Coding: c.224G>A
MANE Select: NM_030578
dbSNP: rs148087680
Type: single nucleotide variant
Location: chr19:41355004 (GRCh38)
Gene constraint: LOEUF 1.518 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.79
Residue 75: the c2 b9-type domain

Full B9D2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

ciliopathy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Joubert syndrome Meckel syndrome

Similar variants

B9D2 p.Arg75Gly Uncertain significance ★ ⚠ same residue
B9D2 p.Gly155Ser Pathogenic/Likely pathogenic ★★ same condition
B9D2 p.Pro74Ser Pathogenic/Likely pathogenic ★★ same condition
B9D2 p.Arg88Cys Uncertain significance ★★ ⚠ same condition
B9D2 p.Gln50His Uncertain significance ★★ ⚠ same condition
B9D2 p.Gly162Cys Uncertain significance ★★ ⚠ same condition
B9D2 p.Pro103Ser Uncertain significance ★★ ⚠ same condition
B9D2 p.Thr44Met Uncertain significance ★★ ⚠ 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/b9d2-p-arg75gln (accessed [today's date]).

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