Is C8B p.Arg296Cys (c.886C>T) pathogenic?

C8B p.Arg296Cys (c.886C>T) is classified Uncertain significance in C8B (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-06-07). AlphaMissense: likely benign (0.1802); Ultra-rare (popmax 0.0493%, mid); Associated with Inborn genetic diseases.

What condition is associated with C8B p.Arg296Cys (c.886C>T)?

C8B p.Arg296Cys (c.886C>T) is associated with Inborn genetic diseases (ClinVar).

How common is C8B p.Arg296Cys (c.886C>T) in the general population?

C8B p.Arg296Cys (c.886C>T) is ultra-rare (popmax 0.0493%, mid) (gnomAD).

What do computational predictors say about C8B p.Arg296Cys (c.886C>T)?

AlphaMissense predicts likely benign (score 0.1802) — an in-silico prediction, not a clinical call.

C8B p.Arg296Cys

c.886C>T · rs147180727 · VCV2068218

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1802 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0493%, mid)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1802	likely benign
REVEL	0.71	pathogenic-leaning
SaProt	LLR -12.94	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.46 · evaluated, not missing
Constraint at this position
Conservation	phyloP 4.5	GERP -1.2, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 37 kb · p 0.016 · regional, not allelic
Overall
CADD	25.6	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 0.0493% Middle Eastern · 3/6,082 alleles

Filtering AF 0.0228% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0196%

Overall 0.00341% 55/1,614,008 alleles · ultra-rare exomes 52/1,461,814 · genomes 3/152,194 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0493%	2,027
South Asian	0.0318%	3,141
Remaining individualsnot grpmax-eligible	0.0032%	31,238
Admixed American	0.00167%	60,006
European (non-Finnish)	0.00161%	62,106
African / African-American	0.00133%	74,912

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.Arg296Cys
Coding: c.886C>T
MANE Select: NM_000066
dbSNP: rs147180727
Type: single nucleotide variant
Location: chr1:56946040 (GRCh38)
Gene constraint: LOEUF 1.18 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.99 · 8 PDB
Residue 296: 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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

C8B p.Arg296His Uncertain significance ★★ ⚠ same residue
C8B p.Ala21Thr Uncertain significance ★★ ⚠ same condition
C8B p.Ala446Val Uncertain significance ★★ ⚠ same condition
C8B p.Arg136Cys Uncertain significance ★★ ⚠ same condition
C8B p.Arg136His Uncertain significance ★★ ⚠ same condition
C8B p.Arg156Gly Uncertain significance ★★ ⚠ same condition
C8B p.Arg428Gln Uncertain significance ★★ ⚠ same condition
C8B p.Arg520Cys 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/c8b-p-arg296cys (accessed [today's date]).

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