Is C8B p.Pro99= (c.297G>A) pathogenic?

C8B p.Pro99= (c.297G>A) is classified Benign/Likely benign in C8B (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-22). Ultra-rare (popmax 0.0213%, afr).

How common is C8B p.Pro99= (c.297G>A) in the general population?

C8B p.Pro99= (c.297G>A) is ultra-rare (popmax 0.0213%, afr) (gnomAD).

C8B p.Pro99=

c.297G>A · rs151032934 · VCV1601099

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0213%, afr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -13	GERP -4.6
Overall
CADD	0.053	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0213% African / African-American · 16/75,046 alleles

Filtering AF 0.0168% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0161%

Overall 0.0386% 623/1,614,100 alleles · ultra-rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.547%	183
Remaining individualsnot grpmax-eligible	0.0416%	2,404
African / African-Americangrpmax	0.0213%	4,690
European (non-Finnish)	0.0189%	5,291
Middle Eastern	0.0165%	6,062
Admixed American	0.00666%	15,006
East Asian	0.00223%	44,858
South Asian	0.0022%	45,544

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: C8B
Protein: p.Pro99=
Coding: c.297G>A
MANE Select: NM_000066
dbSNP: rs151032934
Type: single nucleotide variant
Location: chr1:56956863 (GRCh38)
Gene constraint: LOEUF 1.18 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.99 · 8 PDB
Residue 99: a disulfide bond; a UniProt-annotated variant site (in c8d2); an α-helix; the tsp type-1 1 domain

Full C8B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

C8B p.Pro99Leu Uncertain significance ★★ ⚠ same residue
C8B p.Arg284Ter Pathogenic ★★ same type
C8B p.Arg428Ter Pathogenic ★★ same type
C8B p.Cys508Ter Pathogenic/Likely pathogenic ★★ same type
C8B p.Gln91Ter Pathogenic/Likely pathogenic ★★ same type
C8B p.Trp9Ter Pathogenic ★★ same type
C8B p.Ala21Thr Uncertain significance ★★ ⚠ same type
C8B p.Ala446Val 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/c8b-p-pro99 (accessed [today's date]).

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