Is CFI p.Ala452= (c.1356C>T) pathogenic?

CFI p.Ala452= (c.1356C>T) is classified Likely benign in CFI (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-15). Very rare (popmax 0.000339%, nfe).

How common is CFI p.Ala452= (c.1356C>T) in the general population?

CFI p.Ala452= (c.1356C>T) is very rare (popmax 0.000339%, nfe) (gnomAD).

CFI p.Ala452=

c.1356C>T · rs1192147099 · VCV1953874

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.1	GERP -0.084, phastCons 1
Overall
CADD	6.748	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000339% European (non-Finnish) · 4/1,180,016 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000274% 4/1,461,850 alleles · very rare

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.Ala452=
Coding: c.1356C>T
MANE Select: NM_000204
dbSNP: rs1192147099
Type: single nucleotide variant
Location: chr4:109746295 (GRCh38)
Gene constraint: LOEUF 1.076 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.50 · 2 PDB
Residue 452: an α-helix; a disulfide bond; the peptidase s1 domain

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

Similar variants

CFI p.Ala452Pro Likely pathogenic ★ ⚠ same residue
CFI p.Ala452Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
CFI p.Ala452Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
CFI p.Ala452Asp Uncertain significance ⚠ same residue
CFI c.1429+1G>C Pathogenic/Likely pathogenic ★★ same type
CFI c.57+1G>C Likely pathogenic ★★ same type
CFI c.658+1G>A Likely pathogenic ★★ same type
CFI c.905-1G>C Likely pathogenic ★★ same type

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-ala452 (accessed [today's date]).

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