Is C2 p.Arg510His (c.1529G>A) pathogenic?

C2 p.Arg510His (c.1529G>A) is classified Likely benign in C2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-26). AlphaMissense: likely benign (0.0666); Low-frequency (popmax 1.79%, eas); Associated with age related macular degeneration 14.

What condition is associated with C2 p.Arg510His (c.1529G>A)?

C2 p.Arg510His (c.1529G>A) is associated with age related macular degeneration 14 (ClinVar).

How common is C2 p.Arg510His (c.1529G>A) in the general population?

C2 p.Arg510His (c.1529G>A) is low-frequency (popmax 1.79%, eas) (gnomAD).

What do computational predictors say about C2 p.Arg510His (c.1529G>A)?

AlphaMissense predicts likely benign (score 0.0666) — an in-silico prediction, not a clinical call.

C2 p.Arg510His

c.1529G>A · rs45476300 · VCV356251

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0666 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.79%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

age related macular degeneration 14

Computational evidence

Protein change
AlphaMissense	0.0666	likely benign
REVEL	0.224	benign-leaning
SaProt	LLR -6.47	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.4	GERP -3.8
Regional constraint	o/e 0.84	unconstrained · MANE · 18 kb · p 1.1e-06 · regional, not allelic
Overall
CADD	1.043	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 1.79% East Asian · 803/44,888 alleles

Filtering AF 1.69% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.65%

Overall 0.051% 822/1,613,050 alleles · low-frequency

Ancestry group	Frequency	1 in
East Asiangrpmax	1.79%	56
Remaining individualsnot grpmax-eligible	0.0192%	5,208
South Asian	0.0022%	45,546
African / African-American	0.00133%	75,048
European (non-Finnish)	0.000339%	295,006

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.Arg510His
Coding: c.1529G>A
MANE Select: NM_000063
dbSNP: rs45476300
Type: single nucleotide variant
Location: chr6:31943489 (GRCh38)
Gene constraint: LOEUF 0.909 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.61 · 14 PDB
Residue 510: a disulfide bond; the peptidase s1 domain

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

Disease context

age related macular degeneration 14 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

C2 p.Arg510Cys Uncertain significance ★ ⚠ same residue
C2 p.Arg510= Likely benign ★ 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-arg510his (accessed [today's date]).

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