Is C2 p.Arg421Lys (c.1262G>A) pathogenic?

C2 p.Arg421Lys (c.1262G>A) is classified Conflicting classifications of pathogenicity in C2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2026-01-24). AlphaMissense: likely benign (0.0618); Very rare (popmax 0.00508%, nfe).

How common is C2 p.Arg421Lys (c.1262G>A) in the general population?

C2 p.Arg421Lys (c.1262G>A) is very rare (popmax 0.00508%, nfe) (gnomAD).

What do computational predictors say about C2 p.Arg421Lys (c.1262G>A)?

AlphaMissense predicts likely benign (score 0.0618) — an in-silico prediction, not a clinical call.

C2 p.Arg421Lys

c.1262G>A · rs756916740 · VCV1507034

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0618 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00508%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0618	likely benign
REVEL	0.268	benign-leaning
SaProt	LLR -4.67	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 -0.81	GERP -3.8
Regional constraint	o/e 0.84	unconstrained · MANE · 18 kb · p 1.1e-06 · regional, not allelic
Overall
CADD	0.22	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 0.00508% European (non-Finnish) · 60/1,180,038 alleles

Filtering AF 0.00402% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00362%

Overall 0.00384% 62/1,612,962 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00508%	19,667
Remaining individualsnot grpmax-eligible	0.0016%	62,478
African / African-American	0.00133%	74,930

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: C2
Protein: p.Arg421Lys
Coding: c.1262G>A
MANE Select: NM_000063
dbSNP: rs756916740
Type: single nucleotide variant
Location: chr6:31943001 (GRCh38)
Gene constraint: LOEUF 0.909 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.61 · 14 PDB
Residue 421: the vwfa domain; an α-helix

Full C2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

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C2 p.Ala682Glu Uncertain significance ★★ ⚠ same type
C2 p.Arg124Gln Uncertain significance ★★ ⚠ same type
C2 p.Arg129His Uncertain significance ★★ same type
C2 p.Arg174Cys Uncertain significance ★★ ⚠ same type
C2 p.Arg176Cys 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/c2-p-arg421lys (accessed [today's date]).

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