Is C8B p.Arg561Cys (c.1681C>T) pathogenic?

C8B p.Arg561Cys (c.1681C>T) is classified Uncertain significance in C8B (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-01-30). AlphaMissense: likely benign (0.1977); Ultra-rare (popmax 0.0681%, sas).

How common is C8B p.Arg561Cys (c.1681C>T) in the general population?

C8B p.Arg561Cys (c.1681C>T) is ultra-rare (popmax 0.0681%, sas) (gnomAD).

What do computational predictors say about C8B p.Arg561Cys (c.1681C>T)?

AlphaMissense predicts likely benign (score 0.1977) — an in-silico prediction, not a clinical call.

C8B p.Arg561Cys

c.1681C>T · rs567887687 · VCV1497305

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1977 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0681%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1977	likely benign
REVEL	0.041	moderately benign-leaning
SaProt	LLR -12.29	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.5	GERP 1.9, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 37 kb · p 0.016 · regional, not allelic
Overall
CADD	24.6	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 0.0681% South Asian · 62/91,058 alleles

Filtering AF 0.0544% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0495%

Overall 0.00663% 107/1,613,740 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0681%	1,469
Middle Eastern	0.0339%	2,948
East Asian	0.0156%	6,411
Remaining individualsnot grpmax-eligible	0.0144%	6,942
Ashkenazi Jewishnot grpmax-eligible	0.00676%	14,802
African / African-American	0.00267%	37,514
European (non-Finnish)	0.00186%	53,630
Admixed American	0.00167%	59,988

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.Arg561Cys
Coding: c.1681C>T
MANE Select: NM_000066
dbSNP: rs567887687
Type: single nucleotide variant
Location: chr1:56929499 (GRCh38)
Gene constraint: LOEUF 1.18 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.99 · 8 PDB
Residue 561: a β-strand; the tsp type-1 2 domain; a disulfide bond; a UniProt-annotated variant site (in c8d2)

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

Similar variants

C8B p.Arg561His Uncertain significance ★ ⚠ same residue
C8B p.Arg561= 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
C8B p.Ala21Thr 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-arg561cys (accessed [today's date]).

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