Is CFI p.Arg406His (c.1217G>A) pathogenic?

CFI p.Arg406His (c.1217G>A) is classified Benign/Likely benign in CFI (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-02-02). AlphaMissense: likely benign (0.0786); Common (popmax 9.85%, eas) — too common for a highly-penetrant pathogenic allele; Associated with atypical hemolytic-uremic syndrome with I factor anomaly.

What do computational predictors say about CFI p.Arg406His (c.1217G>A)?

AlphaMissense predicts likely benign (score 0.0786) — an in-silico prediction, not a clinical call.

CFI p.Arg406His

Q: What condition is associated with CFI p.Arg406His (c.1217G>A)?

CFI p.Arg406His (c.1217G>A) is associated with atypical hemolytic-uremic syndrome with I factor anomaly, focal segmental glomerulosclerosis (ClinVar).

Q: How common is CFI p.Arg406His (c.1217G>A) in the general population?

CFI p.Arg406His (c.1217G>A) is common (popmax 9.85%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1217G>A · rs74817407 · VCV347158

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.0786 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 9.85%, eas) — too common for a highly-penetrant pathogenic allele

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

atypical hemolytic-uremic syndrome with I factor anomaly

Computational evidence

Protein change
AlphaMissense	0.0786	likely benign
REVEL	0.684	pathogenic-leaning
SaProt	LLR -5.21	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.9	GERP -0.99
Regional constraint	o/e 1.00	unconstrained · MANE · 61 kb · p 0.95 · regional, not allelic
Overall
CADD	8.495	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 9.85% East Asian · 4,420/44,854 alleles

Filtering AF 9.61% ClinGen BA1/BS1 input FAF95, joint · FAF99 9.51%

Overall 0.747% 12,050/1,613,494 alleles · common

Ancestry group	Frequency	1 in
East Asiangrpmax	9.85%	10
South Asian	4.07%	25
Finnishnot grpmax-eligible	2.34%	43
Remaining individualsnot grpmax-eligible	1.34%	75
Middle Eastern	0.611%	164
Admixed American	0.355%	281
African / African-American	0.123%	814
European (non-Finnish)	0.106%	945

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.Arg406His
Coding: c.1217G>A
MANE Select: NM_000204
dbSNP: rs74817407
Type: single nucleotide variant
Location: chr4:109746434 (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

atypical hemolytic-uremic syndrome with I factor anomaly — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: focal segmental glomerulosclerosis

Similar variants

CFI p.Arg406Cys Uncertain significance ★★ ⚠ 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.905-1G>C Likely pathogenic ★★ same condition
CFI p.Ala258Thr Pathogenic/Likely pathogenic ★★ ⚠ same condition
CFI p.Arg187Ter Pathogenic/Likely pathogenic ★★ same condition
CFI p.Arg474Ter 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-arg406his (accessed [today's date]).

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