Is B9D2 p.Pro49Leu (c.146C>T) pathogenic?

B9D2 p.Pro49Leu (c.146C>T) is classified Uncertain significance in B9D2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-22). AlphaMissense: likely pathogenic (0.5689); Very rare (popmax 0.00653%, nfe).

How common is B9D2 p.Pro49Leu (c.146C>T) in the general population?

B9D2 p.Pro49Leu (c.146C>T) is very rare (popmax 0.00653%, nfe) (gnomAD).

What do computational predictors say about B9D2 p.Pro49Leu (c.146C>T)?

AlphaMissense predicts likely pathogenic (score 0.5689) — an in-silico prediction, not a clinical call.

B9D2 p.Pro49Leu

c.146C>T · VCV4831504

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5689 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00653%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.5689	likely pathogenic
REVEL	0.563	indeterminate
SaProt	LLR -13.50	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 8,816 bp · p 0.14 · regional, not allelic
Overall
CADD	31.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00653% European (non-Finnish) · 77/1,180,004 alleles

Filtering AF 0.0053% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0049%

Overall 0.00514% 83/1,614,038 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00653%	15,325
Remaining individualsnot grpmax-eligible	0.0048%	20,827
South Asian	0.0022%	45,545
African / African-American	0.00133%	74,918

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.Pro49Leu
Coding: c.146C>T
MANE Select: NM_030578
Type: single nucleotide variant
Location: chr19:41357965 (GRCh38)
Gene constraint: LOEUF 1.518 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.79
Residue 49: the c2 b9-type domain

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

Similar variants

B9D2 p.Gly155Ser Pathogenic/Likely pathogenic ★★ same type
B9D2 p.Pro74Ser Pathogenic/Likely pathogenic ★★ same type
B9D2 p.Ser101Arg Pathogenic/Likely pathogenic ★★ same type
B9D2 p.Ala31Glu Uncertain significance ★★ ⚠ same type
B9D2 p.Arg120Gln Uncertain significance ★★ ⚠ same type
B9D2 p.Arg166Cys Uncertain significance ★★ ⚠ same type
B9D2 p.Arg88Cys Uncertain significance ★★ ⚠ same type
B9D2 p.Gln50His Uncertain significance ★★ ⚠ 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/b9d2-p-pro49leu (accessed [today's date]).

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