Is C4B p.Arg895Trp (c.2683C>T) pathogenic?

C4B p.Arg895Trp (c.2683C>T) is classified Uncertain significance in C4B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-07). AlphaMissense: likely benign (0.1138); Ultra-rare (popmax 0.021%, sas).

How common is C4B p.Arg895Trp (c.2683C>T) in the general population?

C4B p.Arg895Trp (c.2683C>T) is ultra-rare (popmax 0.021%, sas) (gnomAD).

What do computational predictors say about C4B p.Arg895Trp (c.2683C>T)?

AlphaMissense predicts likely benign (score 0.1138) — an in-silico prediction, not a clinical call.

C4B p.Arg895Trp

c.2683C>T · VCV3994067

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1138 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.021%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1138	likely benign
REVEL	0.13	moderately benign-leaning
SaProt	LLR -8.77	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.3	GERP -0.64, phastCons 1
Overall
CADD	25.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.021% South Asian · 13/61,762 alleles

Filtering AF 0.0124% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0098%

Overall 0.00267% 24/898,370 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.021%	4,751
Remaining individualsnot grpmax-eligible	0.00541%	18,473
African / African-American	0.00391%	25,556
Admixed American	0.00344%	29,098
European (non-Finnish)	0.000974%	102,667

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.Arg895Trp
Coding: c.2683C>T
MANE Select: NM_007293 · reported on NM_001002029
Type: single nucleotide variant
Location: chr6:32027326 (GRCh38)
Structure: AlphaFold pLDDT 83.56 · 12 PDB
Residue 895: a β-strand

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

Similar variants

C4A p.Arg895Gln Uncertain significance ★ ⚠ same residue
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

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-arg895trp (accessed [today's date]).

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