Is C2 p.Asp661Asn (c.1981G>A) pathogenic?

C2 p.Asp661Asn (c.1981G>A) is classified Uncertain significance in C2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-09-23). AlphaMissense: likely benign (0.1056); Very rare (popmax 0.0078%, nfe); Associated with age related macular degeneration 14.

What condition is associated with C2 p.Asp661Asn (c.1981G>A)?

C2 p.Asp661Asn (c.1981G>A) is associated with age related macular degeneration 14, complement component 2 deficiency (ClinVar).

How common is C2 p.Asp661Asn (c.1981G>A) in the general population?

C2 p.Asp661Asn (c.1981G>A) is very rare (popmax 0.0078%, nfe) (gnomAD).

What do computational predictors say about C2 p.Asp661Asn (c.1981G>A)?

AlphaMissense predicts likely benign (score 0.1056) — an in-silico prediction, not a clinical call.

C2 p.Asp661Asn

c.1981G>A · rs374481091 · VCV905517

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1056 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0078%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

age related macular degeneration 14

Computational evidence

Protein change
AlphaMissense	0.1056	likely benign
REVEL	0.16	moderately benign-leaning
SaProt	LLR -7.98	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 7.6	GERP 1.6, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 18 kb · p 1.1e-06 · regional, not allelic
Overall
CADD	25.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0078% European (non-Finnish) · 92/1,180,030 alleles

Filtering AF 0.00648% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.006%

Overall 0.00595% 96/1,612,960 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0078%	12,826
Remaining individualsnot grpmax-eligible	0.0048%	20,827
African / African-American	0.00133%	74,918

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.Asp661Asn
Coding: c.1981G>A
MANE Select: NM_000063
dbSNP: rs374481091
Type: single nucleotide variant
Location: chr6:31944805 (GRCh38)
Gene constraint: LOEUF 0.909 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.61 · 14 PDB
Residue 661: 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

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C2 p.Arg734Leu Uncertain significance ★★ ⚠ same condition
C2 p.Asp390Ala 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
C2 p.Ser250Cys 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-asp661asn (accessed [today's date]).

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