Is C6 p.Lys763Arg (c.2288A>G) pathogenic?

C6 p.Lys763Arg (c.2288A>G) is classified Benign in C6 (ClinVar, Single submitter, 2 submitters; last evaluated 2026-01-24). AlphaMissense: likely benign (0.0802); Low-frequency (popmax 1.36%, afr).

How common is C6 p.Lys763Arg (c.2288A>G) in the general population?

C6 p.Lys763Arg (c.2288A>G) is low-frequency (popmax 1.36%, afr) (gnomAD).

What do computational predictors say about C6 p.Lys763Arg (c.2288A>G)?

AlphaMissense predicts likely benign (score 0.0802) — an in-silico prediction, not a clinical call.

C6 p.Lys763Arg

c.2288A>G · rs76553178 · VCV1168091

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0802 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.36%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0802	likely benign
REVEL	0.089	moderately benign-leaning
SaProt	LLR -6.71	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 2.3	GERP 1.6, phastCons 0.8
Regional constraint	o/e 1.09	unconstrained · MANE · 60 kb · p 0.0034 · regional, not allelic
Overall
CADD	21.2	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 1.36% African / African-American · 1,021/74,932 alleles

Filtering AF 1.29% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.27%

Overall 0.0727% 1,171/1,610,286 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.36%	73
Admixed American	0.115%	869
Remaining individualsnot grpmax-eligible	0.0994%	1,006
Middle Eastern	0.0188%	5,306
South Asian	0.0033%	30,328
European (non-Finnish)	0.00127%	78,495

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: C6
Protein: p.Lys763Arg
Coding: c.2288A>G
MANE Select: NM_000065
dbSNP: rs76553178
Type: single nucleotide variant
Location: chr5:41153812 (GRCh38)
Gene constraint: LOEUF 1.008 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.72 · 11 PDB
Residue 763: the sushi 2 domain; the 'c5b-binding domain' region; the 'ccp 2' region; an α-helix

Full C6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

C6 p.Arg596Ter Pathogenic/Likely pathogenic ★★ same type
C6 p.Arg606Ter Pathogenic ★★ same type
C6 p.Cys218Ter Pathogenic/Likely pathogenic ★★ same type
C6 p.Tyr683Ter Pathogenic/Likely pathogenic ★★ same type
C6 p.Ala21Val Uncertain significance ★★ ⚠ same type
C6 p.Ala396Gly Uncertain significance ★★ ⚠ same type
C6 p.Ala456Thr Uncertain significance ★★ ⚠ same type
C6 p.Ala500Ser 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/c6-p-lys763arg (accessed [today's date]).

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