Is CFI p.Asp135= (c.405T>C) pathogenic?

CFI p.Asp135= (c.405T>C) is classified Benign/Likely benign in CFI (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-19). Ultra-rare (popmax 0.0219%, nfe); Associated with atypical hemolytic-uremic syndrome with I factor anomaly.

What condition is associated with CFI p.Asp135= (c.405T>C)?

CFI p.Asp135= (c.405T>C) is associated with atypical hemolytic-uremic syndrome with I factor anomaly (ClinVar).

How common is CFI p.Asp135= (c.405T>C) in the general population?

CFI p.Asp135= (c.405T>C) is ultra-rare (popmax 0.0219%, nfe) (gnomAD).

CFI p.Asp135=

c.405T>C · rs375792874 · VCV347172

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0219%, nfe)

Conditions

atypical hemolytic-uremic syndrome with I factor anomaly

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 -0.74	GERP -3.6
Overall
CADD	1.532	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0219% European (non-Finnish) · 259/1,180,000 alleles

Filtering AF 0.0197% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0189%

Overall 0.0173% 280/1,614,038 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0219%	4,556
Remaining individualsnot grpmax-eligible	0.0192%	5,207
African / African-American	0.00934%	10,704
Admixed American	0.00333%	30,005

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.Asp135=
Coding: c.405T>C
MANE Select: NM_000204
dbSNP: rs375792874
Type: single nucleotide variant
Location: chr4:109764614 (GRCh38)
Gene constraint: LOEUF 1.076 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.50 · 2 PDB
Residue 135: a disulfide bond; the srcr domain

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

Disease context

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

Similar variants

CFI p.Asp135Gly Uncertain significance ★ ⚠ 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
CFI p.Arg187Ter Pathogenic/Likely pathogenic ★★ same condition
CFI p.Arg474Ter Pathogenic/Likely 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-asp135 (accessed [today's date]).

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