Is C2 p.Pro583Arg (c.1748C>G) pathogenic?

C2 p.Pro583Arg (c.1748C>G) is classified Uncertain significance in C2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-07-01). AlphaMissense: likely pathogenic (0.9815); Very rare (popmax 0.00212%, nfe).

How common is C2 p.Pro583Arg (c.1748C>G) in the general population?

C2 p.Pro583Arg (c.1748C>G) is very rare (popmax 0.00212%, nfe) (gnomAD).

What do computational predictors say about C2 p.Pro583Arg (c.1748C>G)?

AlphaMissense predicts likely pathogenic (score 0.9815) — an in-silico prediction, not a clinical call.

C2 p.Pro583Arg

c.1748C>G · rs1478487784 · VCV1485986

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9815 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00212%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9815	likely pathogenic · top 3% in C2
REVEL	0.466	indeterminate
SaProt	LLR -14.87	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.6, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 18 kb · p 1.1e-06 · regional, not allelic
Overall
CADD	28.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00212% European (non-Finnish) · 25/1,179,988 alleles

Filtering AF 0.00145% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00123%

Overall 0.00161% 26/1,612,734 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00212%	47,199
African / African-American	0.00134%	74,898

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.Pro583Arg
Coding: c.1748C>G
MANE Select: NM_000063
dbSNP: rs1478487784
Type: single nucleotide variant
Location: chr6:31943931 (GRCh38)
Gene constraint: LOEUF 0.909 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.61 · 14 PDB
Residue 583: the peptidase s1 domain

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

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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-pro583arg (accessed [today's date]).

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