Is CFI p.Ala452Thr (c.1354G>A) pathogenic?

CFI p.Ala452Thr (c.1354G>A) is classified Conflicting classifications of pathogenicity in CFI (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-09-17). AlphaMissense: ambiguous (0.394); Ultra-rare (popmax 0.0178%, eas); Associated with CFI-related disorder.

What condition is associated with CFI p.Ala452Thr (c.1354G>A)?

CFI p.Ala452Thr (c.1354G>A) is associated with CFI-related disorder, atypical hemolytic-uremic syndrome with I factor anomaly (ClinVar).

How common is CFI p.Ala452Thr (c.1354G>A) in the general population?

CFI p.Ala452Thr (c.1354G>A) is ultra-rare (popmax 0.0178%, eas) (gnomAD).

What do computational predictors say about CFI p.Ala452Thr (c.1354G>A)?

AlphaMissense predicts ambiguous (score 0.394) — an in-silico prediction, not a clinical call.

CFI p.Ala452Thr

c.1354G>A · rs750018382 · VCV2057218

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.394 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0178%, eas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

CFI-related disorder

Computational evidence

Protein change
AlphaMissense	0.394	ambiguous
REVEL	0.708	pathogenic-leaning
SaProt	LLR -8.31	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.27 · evaluated, not missing
Constraint at this position
Conservation	phyloP 5.9	GERP 1.7, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 61 kb · p 0.95 · regional, not allelic
Overall
CADD	25.4	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 0.0178% East Asian · 8/44,892 alleles

Filtering AF 0.00883% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00641%

Overall 0.000821% 12/1,461,858 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0178%	5,612
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,602
Admixed American	0.00167%	60,010
Remaining individualsnot grpmax-eligible	0.0016%	62,504
European (non-Finnish)	8.47e-05%	1,180,012

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.Ala452Thr
Coding: c.1354G>A
MANE Select: NM_000204
dbSNP: rs750018382
Type: single nucleotide variant
Location: chr4:109746297 (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

Disease context

Also linked: atypical hemolytic-uremic syndrome with I factor anomaly

Similar variants

CFI p.Ala452Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
CFI p.Ala452Asp Uncertain significance ⚠ same residue
CFI p.Ala452Pro Likely pathogenic ★ ⚠ same residue
CFI p.Ala452= 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

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-ala452thr (accessed [today's date]).

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