Is C2 p.Ser266Trp (c.797C>G) pathogenic?

C2 p.Ser266Trp (c.797C>G) is classified Uncertain significance in C2 (ClinVar, Single submitter, 2 submitters; last evaluated 2022-08-15). AlphaMissense: likely benign (0.2852); Ultra-rare (popmax 0.0367%, amr); Associated with complement component 2 deficiency.

What condition is associated with C2 p.Ser266Trp (c.797C>G)?

C2 p.Ser266Trp (c.797C>G) is associated with complement component 2 deficiency (ClinVar).

How common is C2 p.Ser266Trp (c.797C>G) in the general population?

C2 p.Ser266Trp (c.797C>G) is ultra-rare (popmax 0.0367%, amr) (gnomAD).

What do computational predictors say about C2 p.Ser266Trp (c.797C>G)?

AlphaMissense predicts likely benign (score 0.2852) — an in-silico prediction, not a clinical call.

C2 p.Ser266Trp

Q: How is Immunodeficiency due to a classical component pathway complement deficiency inherited?

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

c.797C>G · rs116568722 · VCV1432615

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2852 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0367%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

complement component 2 deficiency

Computational evidence

Protein change
AlphaMissense	0.2852	likely benign
REVEL	0.362	indeterminate
SaProt	LLR -6.87	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 0.21	GERP -2.1
Regional constraint	o/e 0.84	unconstrained · MANE · 18 kb · p 1.1e-06 · regional, not allelic
Overall
CADD	20.2	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 0.0367% Admixed American · 22/60,000 alleles

Filtering AF 0.0252% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0242%

Overall 0.023% 371/1,614,056 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0367%	2,727
Remaining individualsnot grpmax-eligible	0.0288%	3,473
European (non-Finnish)	0.0277%	3,608
African / African-American	0.00533%	18,755

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.Ser266Trp
Coding: c.797C>G
MANE Select: NM_000063
dbSNP: rs116568722
Type: single nucleotide variant
Location: chr6:31934247 (GRCh38)
Gene constraint: LOEUF 0.909 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.61 · 14 PDB
Residue 266: the vwfa domain

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

Disease context

complement component 2 deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Immunodeficiency due to a classical component pathway complement deficiency (Orphanet):

Inheritance: Autosomal recessive

Similar variants

C2 p.Ser266Leu Uncertain significance ★ ⚠ same residue
C2 p.Ser266= Likely benign ★ same residue
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-ser266trp (accessed [today's date]).

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