Is C2 p.Arg243Cys (c.727C>T) pathogenic?

C2 p.Arg243Cys (c.727C>T) is classified Uncertain significance in C2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-23). AlphaMissense: likely pathogenic (0.7128); Ultra-rare (popmax 0.0104%, nfe).

How common is C2 p.Arg243Cys (c.727C>T) in the general population?

C2 p.Arg243Cys (c.727C>T) is ultra-rare (popmax 0.0104%, nfe) (gnomAD).

What do computational predictors say about C2 p.Arg243Cys (c.727C>T)?

AlphaMissense predicts likely pathogenic (score 0.7128) — an in-silico prediction, not a clinical call.

C2 p.Arg243Cys

c.727C>T · rs370121006 · VCV2176552

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7128 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0104%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7128	likely pathogenic
REVEL	0.688	pathogenic-leaning
SaProt	LLR -8.93	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.7, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 18 kb · p 1.1e-06 · regional, not allelic
Overall
CADD	33.0	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 0.0104% European (non-Finnish) · 123/1,180,026 alleles

Filtering AF 0.00892% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00836%

Overall 0.00824% 133/1,614,146 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0104%	9,594
Admixed American	0.00667%	15,002
Remaining individualsnot grpmax-eligible	0.0048%	20,837
Finnishnot grpmax-eligible	0.00156%	64,034
African / African-American	0.00133%	75,016
South Asian	0.0011%	91,082

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.Arg243Cys
Coding: c.727C>T
MANE Select: NM_000063
dbSNP: rs370121006
Type: single nucleotide variant
Location: chr6:31934177 (GRCh38)
Gene constraint: LOEUF 0.909 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.61 · 14 PDB
Residue 243: a functional site (cleavage; by c1s, masp2 and gzmk)

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

Similar variants

C2 p.Arg243His Uncertain significance ★★ ⚠ same residue
C2 c.1902+5G>A Uncertain significance ★★ same type
C2 c.2029+5G>A Uncertain significance ★★ same type
C2 p.Ala363Thr Uncertain significance ★★ ⚠ same type
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

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-arg243cys (accessed [today's date]).

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