Is C4B p.Arg1291Cys (c.3871C>T) pathogenic?

C4B p.Arg1291Cys (c.3871C>T) is classified Uncertain significance in C4B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-02). AlphaMissense: likely benign (0.1098); Ultra-rare (popmax 0.0467%, amr).

How common is C4B p.Arg1291Cys (c.3871C>T) in the general population?

C4B p.Arg1291Cys (c.3871C>T) is ultra-rare (popmax 0.0467%, amr) (gnomAD).

What do computational predictors say about C4B p.Arg1291Cys (c.3871C>T)?

AlphaMissense predicts likely benign (score 0.1098) — an in-silico prediction, not a clinical call.

C4B p.Arg1291Cys

c.3871C>T · rs574457656 · VCV2476445

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1098 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0467%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1098	likely benign
REVEL	0.171	moderately benign-leaning
SaProt	LLR -10.65	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.94 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.76	GERP 1.8
Overall
CADD	24.9	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 0.0467% Admixed American · 28/60,020 alleles

Filtering AF 0.0331% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0286%

Overall 0.00267% 43/1,612,196 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0467%	2,144
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,578
Remaining individualsnot grpmax-eligible	0.0032%	31,234
East Asian	0.00225%	44,532
African / African-American	0.00133%	75,066
European (non-Finnish)	0.000848%	117,984

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: C4B
Protein: p.Arg1291Cys
Coding: c.3871C>T
MANE Select: NM_007293 · reported on NM_001002029
dbSNP: rs574457656
Type: single nucleotide variant
Location: chr6:32029760 (GRCh38)
Structure: AlphaFold pLDDT 83.56 · 12 PDB
Residue 1291: an α-helix

Full C4B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

C4A c.2944+55T>C Benign/Likely benign ★★ same type
C4A p.Asp1073Gly Benign/Likely benign ★★ same type
C4A p.Pro1120Thr Likely benign ★★ same type
C4B p.Ser1176Asn Benign ★★ ⚠ same type
C4B p.Thr907Ala Benign/Likely benign ★★ same type
C4B c.3230+1G>A Likely pathogenic ★ same type
C4B c.3676+1G>A Likely pathogenic ★ same type
C4A p.Ala1062Val 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/c4b-p-arg1291cys (accessed [today's date]).

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