Is CFI p.His40Pro (c.119A>C) pathogenic?

CFI p.His40Pro (c.119A>C) is classified Uncertain significance in CFI (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-26). AlphaMissense: likely benign (0.131); Absent from gnomAD v4.1; Associated with atypical hemolytic-uremic syndrome.

What condition is associated with CFI p.His40Pro (c.119A>C)?

CFI p.His40Pro (c.119A>C) is associated with atypical hemolytic-uremic syndrome (ClinVar).

How common is CFI p.His40Pro (c.119A>C) in the general population?

CFI p.His40Pro (c.119A>C) is absent from gnomAD v4.1 (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.His40Pro (c.119A>C)?

AlphaMissense predicts likely benign (score 0.131) — an in-silico prediction, not a clinical call.

CFI p.His40Pro

c.119A>C · VCV4280493

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.131 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

atypical hemolytic-uremic syndrome

Computational evidence

Protein change
AlphaMissense	0.131	likely benign
REVEL	0.513	indeterminate
SaProt	LLR -2.53	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.2	GERP -0.68, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 61 kb · p 0.95 · regional, not allelic
Overall
CADD	22.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CFI
Protein: p.His40Pro
Coding: c.119A>C
MANE Select: NM_000204
Type: single nucleotide variant
Location: chr4:109766763 (GRCh38)
Gene constraint: LOEUF 1.076 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.50 · 2 PDB
Residue 40: a disulfide bond

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.His40Arg 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
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-his40pro (accessed [today's date]).

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