Is CFI p.Trp486Arg (c.1456T>C) pathogenic?

CFI p.Trp486Arg (c.1456T>C) is classified Uncertain significance in CFI (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-26). AlphaMissense: likely pathogenic (0.8673); Very rare (popmax 0.0011%, sas); Associated with atypical hemolytic-uremic syndrome.

What condition is associated with CFI p.Trp486Arg (c.1456T>C)?

CFI p.Trp486Arg (c.1456T>C) is associated with atypical hemolytic-uremic syndrome (ClinVar).

How common is CFI p.Trp486Arg (c.1456T>C) in the general population?

CFI p.Trp486Arg (c.1456T>C) is very rare (popmax 0.0011%, sas) (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.Trp486Arg (c.1456T>C)?

AlphaMissense predicts likely pathogenic (score 0.8673) — an in-silico prediction, not a clinical call.

CFI p.Trp486Arg

c.1456T>C · VCV4280566

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8673 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

atypical hemolytic-uremic syndrome

Computational evidence

Protein change
AlphaMissense	0.8673	likely pathogenic
REVEL	0.643	indeterminate
SaProt	LLR -6.95	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.1	GERP 1.3, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 61 kb · p 0.95 · regional, not allelic
Overall
CADD	25.3	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 0.0011% South Asian · 1/91,028 alleles

Overall 0.000137% 2/1,459,066 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,028
European (non-Finnish)	8.49e-05%	1,177,530

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.Trp486Arg
Coding: c.1456T>C
MANE Select: NM_000204
Type: single nucleotide variant
Location: chr4:109742569 (GRCh38)
Gene constraint: LOEUF 1.076 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.50 · 2 PDB
Residue 486: a β-strand; 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 — 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.Trp486Ter Likely pathogenic ★ same residue
CFI p.Trp486Leu Uncertain significance ★ ⚠ 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

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-trp486arg (accessed [today's date]).

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