Is C7 p.Arg220Gln (c.659G>A) pathogenic?

C7 p.Arg220Gln (c.659G>A) is classified Uncertain significance in C7 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-08-13). AlphaMissense: likely benign (0.078); Rare (popmax 0.182%, mid); Associated with complement component 7 deficiency.

What condition is associated with C7 p.Arg220Gln (c.659G>A)?

C7 p.Arg220Gln (c.659G>A) is associated with complement component 7 deficiency (ClinVar).

How common is C7 p.Arg220Gln (c.659G>A) in the general population?

C7 p.Arg220Gln (c.659G>A) is rare (popmax 0.182%, mid) (gnomAD).

What do computational predictors say about C7 p.Arg220Gln (c.659G>A)?

AlphaMissense predicts likely benign (score 0.078) — an in-silico prediction, not a clinical call.

C7 p.Arg220Gln

Q: How is Immunodeficiency due to a late component of complement deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.659G>A · rs369349760 · VCV1040255

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.078 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.182%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

complement component 7 deficiency

Computational evidence

Protein change
AlphaMissense	0.078	likely benign
REVEL	0.35	indeterminate
SaProt	LLR -7.52	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.94	GERP -4.9
Overall
CADD	0.16	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 0.182% Middle Eastern · 11/6,048 alleles

Filtering AF 0.102% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0789%

Overall 0.0129% 207/1,607,242 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.182%	550
Remaining individualsnot grpmax-eligible	0.0353%	2,829
Admixed American	0.027%	3,698
East Asian	0.0269%	3,719
Ashkenazi Jewishnot grpmax-eligible	0.0237%	4,217
European (non-Finnish)	0.0112%	8,912
African / African-American	0.00535%	18,694
South Asian	0.00335%	29,882

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: C7
Protein: p.Arg220Gln
Coding: c.659G>A
MANE Select: NM_001565 · reported on NM_000587
dbSNP: rs369349760
Type: single nucleotide variant
Location: chr5:40945289 (GRCh38)
Structure: AlphaFold pLDDT 89.67 · 6 PDB

Full C7 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

complement component 7 deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Immunodeficiency due to a late component of complement deficiency (Orphanet):

Inheritance: Autosomal recessive

Similar variants

C7 p.Arg220Trp Uncertain significance ★★ ⚠ same residue
C7 c.281-1G>T Pathogenic/Likely pathogenic ★★ same condition
C7 c.63-1G>A Pathogenic ★★ same condition
C7 p.Gly379Arg Pathogenic/Likely pathogenic ★★ ⚠ same condition
C7 p.Trp205Ter Pathogenic/Likely pathogenic ★★ same condition
C7 p.Arg402Gln Uncertain significance ★★ ⚠ same condition
C7 p.Arg618Trp Uncertain significance ★★ ⚠ same condition
C7 p.Asn202Ser 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/c7-p-arg220gln (accessed [today's date]).

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