Is C2 p.Arg129His (c.386G>A) pathogenic?

C2 p.Arg129His (c.386G>A) is classified Uncertain significance in C2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2024-10-23). AlphaMissense: ambiguous (0.4218); Ultra-rare (popmax 0.024%, afr); Associated with age related macular degeneration 14.

What condition is associated with C2 p.Arg129His (c.386G>A)?

C2 p.Arg129His (c.386G>A) is associated with age related macular degeneration 14, complement component 2 deficiency (ClinVar).

How common is C2 p.Arg129His (c.386G>A) in the general population?

C2 p.Arg129His (c.386G>A) is ultra-rare (popmax 0.024%, afr) (gnomAD).

What do computational predictors say about C2 p.Arg129His (c.386G>A)?

AlphaMissense predicts ambiguous (score 0.4218) — an in-silico prediction, not a clinical call.

C2 p.Arg129His

c.386G>A · rs367996721 · VCV906979

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

ambiguous

0.4218 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.024%, afr)

Conditions

age related macular degeneration 14

Computational evidence

Protein change
AlphaMissense	0.4218	ambiguous
REVEL	0.575	indeterminate
SaProt	LLR -10.83	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 18 kb · p 1.1e-06 · regional, not allelic
Overall
CADD	27.1	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 0.024% African / African-American · 18/75,076 alleles

Filtering AF 0.0154% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0128%

Overall 0.00607% 98/1,614,236 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0405%	2,467
Remaining individualsnot grpmax-eligible	0.0304%	3,290
African / African-Americangrpmax	0.024%	4,171
Admixed American	0.0217%	4,617
Middle Eastern	0.0165%	6,060
East Asian	0.00446%	22,437
South Asian	0.00329%	30,363
European (non-Finnish)	0.00254%	39,335

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg129His
Coding: c.386G>A
MANE Select: NM_000063
dbSNP: rs367996721
Type: single nucleotide variant
Location: chr6:31928861 (GRCh38)
Gene constraint: LOEUF 0.909 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.61 · 14 PDB
Residue 129: a disulfide bond; the sushi 2 domain; a β-strand

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.Arg129Cys Uncertain significance ★ ⚠ same residue
C2 c.1902+5G>A 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
C2 p.Phe95Val 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-arg129his (accessed [today's date]).

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