Is B9D2 p.Pro103Ser (c.307C>T) pathogenic?

B9D2 p.Pro103Ser (c.307C>T) is classified Uncertain significance in B9D2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-09-30). AlphaMissense: likely benign (0.2247); Ultra-rare (popmax 0.0164%, mid); Associated with Joubert syndrome.

What condition is associated with B9D2 p.Pro103Ser (c.307C>T)?

B9D2 p.Pro103Ser (c.307C>T) is associated with Joubert syndrome, Meckel syndrome, type 10, Meckel syndrome (ClinVar).

How common is B9D2 p.Pro103Ser (c.307C>T) in the general population?

B9D2 p.Pro103Ser (c.307C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about B9D2 p.Pro103Ser (c.307C>T)?

AlphaMissense predicts likely benign (score 0.2247) — an in-silico prediction, not a clinical call.

B9D2 p.Pro103Ser

c.307C>T · rs1320885309 · VCV2059724

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2247 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Joubert syndrome

Computational evidence

Protein change
AlphaMissense	0.2247	likely benign
REVEL	0.645	pathogenic-leaning
SaProt	LLR -11.74	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 1.1, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 8,816 bp · p 0.14 · regional, not allelic
Overall
CADD	27.9	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 0.0164% Middle Eastern · 1/6,082 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000248% 4/1,613,274 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,082
Admixed American	0.00167%	59,970
European (non-Finnish)	0.00017%	589,908

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.Pro103Ser
Coding: c.307C>T
MANE Select: NM_030578
dbSNP: rs1320885309
Type: single nucleotide variant
Location: chr19:41354921 (GRCh38)
Gene constraint: LOEUF 1.518 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.79
Residue 103: the c2 b9-type domain

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

Disease context

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

Also linked: Meckel syndrome, type 10 Meckel syndrome

Similar variants

B9D2 p.Pro103= Likely benign ★★ same residue
B9D2 p.Pro103Leu Uncertain significance ★ ⚠ same residue
B9D2 p.Gly155Ser Pathogenic/Likely pathogenic ★★ same condition
B9D2 p.Pro74Ser Pathogenic/Likely pathogenic ★★ same condition
B9D2 p.Ser101Arg Pathogenic/Likely pathogenic ★★ ⚠ same condition
B9D2 p.Arg166Cys Uncertain significance ★★ ⚠ same condition
B9D2 p.Arg88Cys Uncertain significance ★★ ⚠ same condition
B9D2 p.Gln50His 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-pro103ser (accessed [today's date]).

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