Is CFI p.Arg406Cys (c.1216C>T) pathogenic?

CFI p.Arg406Cys (c.1216C>T) is classified Uncertain significance in CFI (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-09-17). AlphaMissense: ambiguous (0.3565); Ultra-rare (popmax 0.0521%, afr); Associated with complement factor I deficiency.

What condition is associated with CFI p.Arg406Cys (c.1216C>T)?

CFI p.Arg406Cys (c.1216C>T) is associated with complement factor I deficiency, atypical hemolytic-uremic syndrome with I factor anomaly, age related macular degeneration 13 (ClinVar).

How common is CFI p.Arg406Cys (c.1216C>T) in the general population?

CFI p.Arg406Cys (c.1216C>T) is ultra-rare (popmax 0.0521%, afr) (gnomAD).

How is Immunodeficiency with factor I anomaly inherited?

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

What do computational predictors say about CFI p.Arg406Cys (c.1216C>T)?

AlphaMissense predicts ambiguous (score 0.3565) — an in-silico prediction, not a clinical call.

CFI p.Arg406Cys

c.1216C>T · rs181729783 · VCV1356015

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

ambiguous

0.3565 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0521%, afr)

Conditions

complement factor I deficiency

Computational evidence

Protein change
AlphaMissense	0.3565	ambiguous
REVEL	0.433	indeterminate
SaProt	LLR -9.91	tolerated
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.84 · evaluated, not missing
Constraint at this position
Conservation	phyloP -0.15	GERP -2
Regional constraint	o/e 1.00	unconstrained · MANE · 61 kb · p 0.95 · regional, not allelic
Overall
CADD	17.11	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 0.0521% African / African-American · 39/74,888 alleles

Filtering AF 0.0392% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0346%

Overall 0.00787% 127/1,613,562 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0521%	1,920
Admixed American	0.0467%	2,142
Middle Eastern	0.0165%	6,060
Remaining individualsnot grpmax-eligible	0.0144%	6,943
South Asian	0.00879%	11,382
European (non-Finnish)	0.00356%	28,091

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: CFI
Protein: p.Arg406Cys
Coding: c.1216C>T
MANE Select: NM_000204
dbSNP: rs181729783
Type: single nucleotide variant
Location: chr4:109746435 (GRCh38)
Gene constraint: LOEUF 1.076 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.50 · 2 PDB
Residue 406: a disulfide bond; the peptidase s1 domain

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

Disease context

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

Also linked: atypical hemolytic-uremic syndrome with I factor anomaly age related macular degeneration 13

For Immunodeficiency with factor I anomaly (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Childhood

Similar variants

CFI p.Arg406His Benign/Likely benign ★★ ⚠ same residue
CFI p.Arg406= Likely benign ★ same residue
CFI c.1429+1G>C Pathogenic/Likely pathogenic ★★ same condition
CFI c.57+1G>C Likely pathogenic ★★ same condition
CFI c.658+1G>A Likely pathogenic ★★ same condition
CFI c.905-1G>C Likely pathogenic ★★ same condition
CFI p.Ala258Thr Pathogenic/Likely pathogenic ★★ ⚠ same condition
CFI p.Arg187Ter Pathogenic/Likely 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/cfi-p-arg406cys (accessed [today's date]).

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