Is C2 p.Arg243His (c.728G>A) pathogenic?

C2 p.Arg243His (c.728G>A) is classified Uncertain significance in C2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-04). AlphaMissense: likely benign (0.3164); Very rare (popmax 0.000932%, nfe).

How common is C2 p.Arg243His (c.728G>A) in the general population?

C2 p.Arg243His (c.728G>A) is very rare (popmax 0.000932%, nfe) (gnomAD).

What do computational predictors say about C2 p.Arg243His (c.728G>A)?

AlphaMissense predicts likely benign (score 0.3164) — an in-silico prediction, not a clinical call.

C2 p.Arg243His

c.728G>A · rs201130773 · VCV1375438

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.3164 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000932%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.3164	likely benign
REVEL	0.471	indeterminate
SaProt	LLR -5.58	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	Δ0.21	acceptor loss, 12 bp away · masked 0 · deltas
Pangolin	Δ0.22	loss · gain 0.01 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 18 kb · p 1.1e-06 · regional, not allelic
Overall
CADD	32.0	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 0.000932% European (non-Finnish) · 11/1,180,024 alleles

Filtering AF 0.0005% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000366%

Overall 0.000681% 11/1,614,206 alleles · very rare

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.Arg243His
Coding: c.728G>A
MANE Select: NM_000063
dbSNP: rs201130773
Type: single nucleotide variant
Location: chr6:31934178 (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.Arg243Cys 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-arg243his (accessed [today's date]).

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