Is C2 p.Ala341= (c.1023G>A) pathogenic?

C2 p.Ala341= (c.1023G>A) is classified Benign/Likely benign in C2 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-04). Common (popmax 19%, afr) — too common for a highly-penetrant pathogenic allele; Associated with age related macular degeneration 14.

What condition is associated with C2 p.Ala341= (c.1023G>A)?

C2 p.Ala341= (c.1023G>A) is associated with age related macular degeneration 14, complement component 2 deficiency (ClinVar).

C2 p.Ala341=

Q: How common is C2 p.Ala341= (c.1023G>A) in the general population?

C2 p.Ala341= (c.1023G>A) is common (popmax 19%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1023G>A · rs1042663 · VCV356245

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Common

common (popmax 19%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

age related macular degeneration 14

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.011	strongly benign-leaning
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.54 · evaluated, not missing
Constraint at this position
Conservation	phyloP 2.8	GERP -1.8, phastCons 1
Overall
CADD	9.542	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 19% African / African-American · 14,214/74,828 alleles

Filtering AF 18.7% ClinGen BA1/BS1 input FAF95, joint · FAF99 18.6%

Overall 9.96% 160,642/1,612,312 alleles · common exomes 142,895/1,460,448 · genomes 17,747/151,864 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	19%	5
South Asian	15.5%	6
Remaining individualsnot grpmax-eligible	11%	9
European (non-Finnish)	9.44%	11
Admixed American	8.07%	12
Middle Eastern	7.27%	14
East Asian	6.99%	14
Finnishnot grpmax-eligible	6.38%	16
Ashkenazi Jewishnot grpmax-eligible	5.57%	18
Amishnot grpmax-eligible	4.62%	22

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.Ala341=
Coding: c.1023G>A
MANE Select: NM_000063
dbSNP: rs1042663
Type: single nucleotide variant
Location: chr6:31937353 (GRCh38)
Gene constraint: LOEUF 0.909 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.61 · 14 PDB
Residue 341: the vwfa domain; an α-helix

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.Ala341Glu 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-ala341 (accessed [today's date]).

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