Is C4B p.Arg916Gln (c.2747G>A) pathogenic?

C4B p.Arg916Gln (c.2747G>A) is classified Uncertain significance in C4B (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-04). AlphaMissense: likely benign (0.0927); Low-frequency (popmax 1.12%, afr).

How common is C4B p.Arg916Gln (c.2747G>A) in the general population?

C4B p.Arg916Gln (c.2747G>A) is low-frequency (popmax 1.12%, afr) (gnomAD).

What do computational predictors say about C4B p.Arg916Gln (c.2747G>A)?

AlphaMissense predicts likely benign (score 0.0927) — an in-silico prediction, not a clinical call.

C4B p.Arg916Gln

c.2747G>A · rs202120998 · VCV2227159

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0927 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.12%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0927	likely benign
REVEL	0.078	moderately benign-leaning
SaProt	LLR -5.96	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 4.3	GERP -1.6, phastCons 1
Overall
CADD	19.58	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 1.12% African / African-American · 160/14,264 alleles

Filtering AF 0.98% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.926%

Overall 0.0304% 215/706,478 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.12%	89
Admixed American	0.176%	567
Remaining individualsnot grpmax-eligible	0.0822%	1,216
South Asian	0.00309%	32,332
European (non-Finnish)	0.000352%	283,930

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.Arg916Gln
Coding: c.2747G>A
MANE Select: NM_007293 · reported on NM_001002029
dbSNP: rs202120998
Type: single nucleotide variant
Location: chr6:32027390 (GRCh38)
Structure: AlphaFold pLDDT 83.56 · 12 PDB
Residue 916: a β-strand

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-arg916gln (accessed [today's date]).

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