Is B9D2 p.Arg166Cys (c.496C>T) pathogenic?

B9D2 p.Arg166Cys (c.496C>T) is classified Uncertain significance in B9D2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-11-19). AlphaMissense: ambiguous (0.4757); Ultra-rare (popmax 0.0184%, nfe); Associated with Meckel syndrome, type 10.

What condition is associated with B9D2 p.Arg166Cys (c.496C>T)?

B9D2 p.Arg166Cys (c.496C>T) is associated with Meckel syndrome, type 10 (ClinVar).

How common is B9D2 p.Arg166Cys (c.496C>T) in the general population?

B9D2 p.Arg166Cys (c.496C>T) is ultra-rare (popmax 0.0184%, nfe) (gnomAD).

What do computational predictors say about B9D2 p.Arg166Cys (c.496C>T)?

AlphaMissense predicts ambiguous (score 0.4757) — an in-silico prediction, not a clinical call.

B9D2 p.Arg166Cys

c.496C>T · rs749611100 · VCV281470

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.4757 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0184%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Meckel syndrome, type 10

Computational evidence

Protein change
AlphaMissense	0.4757	ambiguous
REVEL	0.708	pathogenic-leaning
SaProt	LLR -11.90	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.2	GERP 1.3, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 8,816 bp · p 0.14 · regional, not allelic
Overall
CADD	32.0	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 0.0184% European (non-Finnish) · 217/1,180,036 alleles

Filtering AF 0.0164% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0156%

Overall 0.0143% 230/1,613,934 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0184%	5,438
Remaining individualsnot grpmax-eligible	0.008%	12,497
South Asian	0.00439%	22,773
African / African-American	0.004%	24,977
Admixed American	0.00167%	60,006

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.Arg166Cys
Coding: c.496C>T
MANE Select: NM_030578
dbSNP: rs749611100
Type: single nucleotide variant
Location: chr19:41354732 (GRCh38)
Gene constraint: LOEUF 1.518 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.79

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

Disease context

Meckel syndrome, type 10 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

B9D2 p.Arg166Gly Uncertain significance ★ ⚠ same residue
B9D2 p.Ser101Arg Pathogenic/Likely pathogenic ★★ same condition
B9D2 p.Gly162Cys Uncertain significance ★★ ⚠ same condition
B9D2 p.Pro103Ser Uncertain significance ★★ ⚠ same condition
B9D2 c.214+25T>G Benign ★★ same condition
B9D2 c.88+6C>T Benign/Likely benign ★★ same condition
B9D2 c.-4-40C>G Benign ★★ same condition
B9D2 c.*18G>A Benign ★★ 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-arg166cys (accessed [today's date]).

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