Is C8B p.Ser290Arg (c.870C>G) pathogenic?

C8B p.Ser290Arg (c.870C>G) is classified Uncertain significance in C8B (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-12). AlphaMissense: likely pathogenic (0.603); Very rare (popmax 0.000169%, nfe).

How common is C8B p.Ser290Arg (c.870C>G) in the general population?

C8B p.Ser290Arg (c.870C>G) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about C8B p.Ser290Arg (c.870C>G)?

AlphaMissense predicts likely pathogenic (score 0.603) — an in-silico prediction, not a clinical call.

C8B p.Ser290Arg

c.870C>G · rs771744350 · VCV2080963

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.603 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.603	likely pathogenic
REVEL	0.612	indeterminate
SaProt	LLR -9.12	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.6	GERP -1.2, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 37 kb · p 0.016 · regional, not allelic
Overall
CADD	6.315	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 0.000169% European (non-Finnish) · 2/1,179,988 alleles

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

Overall 0.000137% 2/1,461,770 alleles · very rare

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.Ser290Arg
Coding: c.870C>G
MANE Select: NM_000066
dbSNP: rs771744350
Type: single nucleotide variant
Location: chr1:56946056 (GRCh38)
Gene constraint: LOEUF 1.18 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.99 · 8 PDB
Residue 290: a UniProt-annotated variant site (in c8d2); a β-strand; the macpf domain

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

Similar variants

C8B p.Ser290Asn Uncertain significance ★ ⚠ same residue
C8B p.Ser290Thr Uncertain significance ★ ⚠ same residue
C8B p.Ser290= Likely benign ★ 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

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-ser290arg (accessed [today's date]).

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