Is CFI p.Pro553Ser (c.1657C>T) pathogenic?

CFI p.Pro553Ser (c.1657C>T) is classified Benign/Likely benign in CFI (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-04-01). AlphaMissense: likely benign (0.1453); Rare (popmax 0.33%, nfe); Associated with CFI-related disorder.

What condition is associated with CFI p.Pro553Ser (c.1657C>T)?

CFI p.Pro553Ser (c.1657C>T) is associated with CFI-related disorder, atypical hemolytic-uremic syndrome with I factor anomaly (ClinVar).

How common is CFI p.Pro553Ser (c.1657C>T) in the general population?

CFI p.Pro553Ser (c.1657C>T) is rare (popmax 0.33%, nfe) (gnomAD).

What do computational predictors say about CFI p.Pro553Ser (c.1657C>T)?

AlphaMissense predicts likely benign (score 0.1453) — an in-silico prediction, not a clinical call.

CFI p.Pro553Ser

c.1657C>T · rs113460688 · VCV347146

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.1453 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.33%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

CFI-related disorder

Computational evidence

Protein change
AlphaMissense	0.1453	likely benign
REVEL	0.165	moderately benign-leaning
SaProt	LLR -6.90	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.2	GERP 0.81, phastCons 0.63
Regional constraint	o/e 1.00	unconstrained · MANE · 61 kb · p 0.95 · regional, not allelic
Overall
CADD	16.57	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 0.33% European (non-Finnish) · 3,895/1,179,994 alleles

Filtering AF 0.321% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.318%

Overall 0.259% 4,177/1,614,134 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.33%	303
Remaining individualsnot grpmax-eligible	0.298%	336
Amishnot grpmax-eligible	0.11%	912
Middle Eastern	0.0825%	1,212
African / African-American	0.0413%	2,421
Finnishnot grpmax-eligible	0.0312%	3,202
Admixed American	0.0267%	3,750
South Asian	0.0231%	4,338
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606
East Asian	0.00223%	44,880

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.Pro553Ser
Coding: c.1657C>T
MANE Select: NM_000204
dbSNP: rs113460688
Type: single nucleotide variant
Location: chr4:109740988 (GRCh38)
Gene constraint: LOEUF 1.076 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.50 · 2 PDB
Residue 553: 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 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
CFI p.Arg187Ter Pathogenic/Likely pathogenic ★★ same condition
CFI p.Arg474Ter Pathogenic/Likely pathogenic ★★ same condition
CFI p.Trp145Ter Pathogenic ★★ same condition
CFI c.773-3C>T 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-pro553ser (accessed [today's date]).

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