Is C2 p.Arg593Gln (c.1778G>A) pathogenic?

C2 p.Arg593Gln (c.1778G>A) is classified Conflicting classifications of pathogenicity in C2 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-03-25). AlphaMissense: likely benign (0.221); Rare (popmax 0.368%, afr); Associated with age related macular degeneration 14.

What condition is associated with C2 p.Arg593Gln (c.1778G>A)?

C2 p.Arg593Gln (c.1778G>A) is associated with age related macular degeneration 14, complement component 2 deficiency (ClinVar).

How common is C2 p.Arg593Gln (c.1778G>A) in the general population?

C2 p.Arg593Gln (c.1778G>A) is rare (popmax 0.368%, afr) (gnomAD).

What do computational predictors say about C2 p.Arg593Gln (c.1778G>A)?

AlphaMissense predicts likely benign (score 0.221) — an in-silico prediction, not a clinical call.

C2 p.Arg593Gln

c.1778G>A · rs150878060 · VCV369520

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.221 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.368%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

age related macular degeneration 14

Computational evidence

Protein change
AlphaMissense	0.221	likely benign
REVEL	0.572	indeterminate
SaProt	LLR -5.94	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	GERP 0.4, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 18 kb · p 1.1e-06 · regional, not allelic
Overall
CADD	30.0	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 0.368% African / African-American · 276/75,030 alleles

Filtering AF 0.332% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.318%

Overall 0.0201% 325/1,612,984 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.368%	272
Admixed American	0.04%	2,501
Remaining individualsnot grpmax-eligible	0.0176%	5,681
East Asian	0.00223%	44,892
South Asian	0.0011%	91,084
European (non-Finnish)	0.00102%	98,335

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.Arg593Gln
Coding: c.1778G>A
MANE Select: NM_000063
dbSNP: rs150878060
Type: single nucleotide variant
Location: chr6:31943961 (GRCh38)
Gene constraint: LOEUF 0.909 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.61 · 14 PDB
Residue 593: a disulfide bond; the peptidase s1 domain

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

Disease context

Also linked: complement component 2 deficiency

Similar variants

C2 p.Arg593Trp Uncertain significance ★★ ⚠ same residue
C2 c.1902+5G>A Uncertain significance ★★ same condition
C2 p.Arg129His Uncertain significance ★★ ⚠ same condition
C2 p.Arg734Leu Uncertain significance ★★ ⚠ same condition
C2 p.Asp390Ala Uncertain significance ★★ ⚠ same condition
C2 p.Asp661Asn Uncertain significance ★★ ⚠ same condition
C2 p.Lys572Asn Uncertain significance ★★ ⚠ same condition
C2 p.Phe273= Uncertain significance ★★ same condition

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-arg593gln (accessed [today's date]).

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