Is CFI p.Ser545Arg (c.1635T>A) pathogenic?

CFI p.Ser545Arg (c.1635T>A) is classified Likely pathogenic in CFI (ClinVar, Single submitter, 1 submitter; last evaluated 2026-09-17). AlphaMissense: likely pathogenic (0.998); Very rare (popmax 8.47e-05%, nfe); Associated with atypical hemolytic-uremic syndrome.

What condition is associated with CFI p.Ser545Arg (c.1635T>A)?

CFI p.Ser545Arg (c.1635T>A) is associated with atypical hemolytic-uremic syndrome (ClinVar).

How common is CFI p.Ser545Arg (c.1635T>A) in the general population?

CFI p.Ser545Arg (c.1635T>A) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

How is Atypical hemolytic uremic syndrome inherited?

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

What do computational predictors say about CFI p.Ser545Arg (c.1635T>A)?

AlphaMissense predicts likely pathogenic (score 0.998) — an in-silico prediction, not a clinical call.

CFI p.Ser545Arg

c.1635T>A · VCV4280544

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.998 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

atypical hemolytic-uremic syndrome

Computational evidence

Protein change
AlphaMissense	0.998	likely pathogenic ✓ concordant with ClinVar · top 1% in CFI
REVEL	0.93	moderately pathogenic-leaning
SaProt	LLR -15.84	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.23	GERP -3.5, phastCons 0.55
Regional constraint	o/e 1.00	unconstrained · MANE · 61 kb · p 0.95 · regional, not allelic
Overall
CADD	22.4	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 8.47e-05% European (non-Finnish) · 1/1,179,992 alleles

Overall 6.2e-05% 1/1,614,128 alleles · very rare exomes 1/1,461,862 · genomes 0/152,266 · joint denominator

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.Ser545Arg
Coding: c.1635T>A
MANE Select: NM_000204
Type: single nucleotide variant
Location: chr4:109741010 (GRCh38)
Gene constraint: LOEUF 1.076 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.50 · 2 PDB
Residue 545: the peptidase s1 domain

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

Disease context

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

For Atypical hemolytic uremic syndrome (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, Not applicable
Onset: All ages
Prevalence: 1-9 / 1 000 000 (United States)

Similar variants

CFI p.Ser545= Likely benign ★ same residue
CFI c.1429+1G>C Pathogenic/Likely pathogenic ★★ same condition
CFI p.Ala384Thr Uncertain significance ★★ ⚠ same condition
CFI p.Arg168Gly Uncertain significance ★★ ⚠ same condition
CFI p.Arg389His Uncertain significance ★★ ⚠ same condition
CFI p.Arg448Cys Uncertain significance ★★ ⚠ same condition
CFI p.Asn70Thr Uncertain significance ★★ ⚠ same condition
CFI p.Asp208Asn Uncertain significance ★★ ⚠ 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-ser545arg (accessed [today's date]).

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