Is CFI p.Pro64Leu (c.191C>T) pathogenic?

CFI p.Pro64Leu (c.191C>T) is classified Conflicting classifications of pathogenicity in CFI (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-09-17). AlphaMissense: likely benign (0.2452); Rare (popmax 0.11%, amr); Associated with complement factor I deficiency.

What condition is associated with CFI p.Pro64Leu (c.191C>T)?

CFI p.Pro64Leu (c.191C>T) is associated with complement factor I deficiency (ClinVar).

How common is CFI p.Pro64Leu (c.191C>T) in the general population?

CFI p.Pro64Leu (c.191C>T) is rare (popmax 0.11%, amr) (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.Pro64Leu (c.191C>T)?

AlphaMissense predicts likely benign (score 0.2452) — an in-silico prediction, not a clinical call.

CFI p.Pro64Leu

c.191C>T · rs773187287 · VCV2055075

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.2452 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.11%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

complement factor I deficiency

Computational evidence

Protein change
AlphaMissense	0.2452	likely benign
REVEL	0.703	pathogenic-leaning
SaProt	LLR -8.21	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 12	GERP 1.9, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 61 kb · p 0.95 · regional, not allelic
Overall
CADD	31.0	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 0.11% Admixed American · 66/59,988 alleles

Filtering AF 0.0887% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0809%

Overall 0.00799% 129/1,613,996 alleles · rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.11%	909
South Asian	0.011%	9,108
Remaining individualsnot grpmax-eligible	0.0048%	20,827
European (non-Finnish)	0.00407%	24,584
African / African-American	0.00267%	37,456

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.Pro64Leu
Coding: c.191C>T
MANE Select: NM_000204
dbSNP: rs773187287
Type: single nucleotide variant
Location: chr4:109766691 (GRCh38)
Gene constraint: LOEUF 1.076 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.50 · 2 PDB
Residue 64: a disulfide bond; the kazal-like domain; a UniProt-annotated variant site (in ahus3); an α-helix

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

For Immunodeficiency with factor I anomaly (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Childhood

Similar variants

CFI p.Pro64= 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
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-pro64leu (accessed [today's date]).

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