Is CFD p.Gly216Ser (c.646G>A) pathogenic?

CFD p.Gly216Ser (c.646G>A) is classified Uncertain significance in CFD (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-01). AlphaMissense: likely benign (0.113); Absent from gnomAD v4.1; Associated with recurrent Neisseria infections due to factor D deficiency.

What condition is associated with CFD p.Gly216Ser (c.646G>A)?

CFD p.Gly216Ser (c.646G>A) is associated with recurrent Neisseria infections due to factor D deficiency (ClinVar).

How common is CFD p.Gly216Ser (c.646G>A) in the general population?

CFD p.Gly216Ser (c.646G>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CFD p.Gly216Ser (c.646G>A)?

AlphaMissense predicts likely benign (score 0.113) — an in-silico prediction, not a clinical call.

CFD p.Gly216Ser

Q: How is Recurrent Neisseria infections due to factor D deficiency inherited?

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

c.646G>A · VCV3898024

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.113 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,531,782)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

recurrent Neisseria infections due to factor D deficiency

Computational evidence

Protein change
AlphaMissense	0.113	likely benign
REVEL	0.673	pathogenic-leaning
SaProt	LLR -11.18	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.6	GERP -1, phastCons 1
Regional constraint	o/e 1.40	unconstrained · MANE · 3,545 bp · p 9.1e-15 · regional, not allelic
Overall
CADD	22.1	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

No allele count reported in gnomAD v4.1 (AN 1,531,782). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: CFD
Protein: p.Gly216Ser
Coding: c.646G>A
MANE Select: NM_001928
Type: single nucleotide variant
Location: chr19:863122 (GRCh38)
Gene constraint: LOEUF 1.948 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 91.19 · 40 PDB
Residue 216: a disulfide bond; the peptidase s1 domain

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

Disease context

recurrent Neisseria infections due to factor D deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Recurrent Neisseria infections due to factor D deficiency (Orphanet):

Inheritance: Autosomal recessive

Similar variants

CFD p.Gly216Asp Uncertain significance ★★ ⚠ same residue
CFD p.Gly216Ala Uncertain significance ★ ⚠ same residue
CFD p.Gly216= Likely benign ★ same residue
CFD c.212+2T>G Likely pathogenic ★★ same condition
CFD c.56-1G>C Likely pathogenic ★★ same condition
CFD p.Tyr95Ter Pathogenic ★★ same condition
CFD c.213-1G>C Likely pathogenic ★ same condition
CFD p.Ser42Ter Pathogenic ★ 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/cfd-p-gly216ser (accessed [today's date]).

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