Is C2 p.Ala682= (c.2046A>G) pathogenic?

C2 p.Ala682= (c.2046A>G) is classified Benign/Likely benign in C2 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-04-01). Low-frequency (popmax 1.44%, eas); Associated with age related macular degeneration 14.

What condition is associated with C2 p.Ala682= (c.2046A>G)?

C2 p.Ala682= (c.2046A>G) is associated with age related macular degeneration 14, complement component 2 deficiency (ClinVar).

How common is C2 p.Ala682= (c.2046A>G) in the general population?

C2 p.Ala682= (c.2046A>G) is low-frequency (popmax 1.44%, eas) (gnomAD).

C2 p.Ala682=

c.2046A>G · rs45507391 · VCV356258

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.44%, eas)

Conditions

age related macular degeneration 14

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.167	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.8	GERP -3.5
Overall
CADD	2.29	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.44% East Asian · 645/44,874 alleles

Filtering AF 1.35% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.31%

Overall 0.114% 1,835/1,613,054 alleles · low-frequency exomes 1,573/1,460,772 · genomes 262/152,282 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	1.44%	70
Finnishnot grpmax-eligible	0.734%	136
Admixed American	0.626%	160
Remaining individualsnot grpmax-eligible	0.162%	619
South Asian	0.0362%	2,760
Middle Eastern	0.033%	3,031
African / African-American	0.02%	5,002
European (non-Finnish)	0.017%	5,871

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.Ala682=
Coding: c.2046A>G
MANE Select: NM_000063
dbSNP: rs45507391
Type: single nucleotide variant
Location: chr6:31944996 (GRCh38)
Gene constraint: LOEUF 0.909 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.61 · 14 PDB
Residue 682: a β-strand; 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.Ala682Glu Uncertain significance ★★ ⚠ same residue
C2 p.Ala682Gly 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

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-ala682 (accessed [today's date]).

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