Is CFI p.Arg339Leu (c.1016G>T) pathogenic?

CFI p.Arg339Leu (c.1016G>T) is classified Conflicting classifications of pathogenicity in CFI (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-09-26). AlphaMissense: likely pathogenic (0.9022); Very rare (popmax 0.000424%, nfe); Associated with atypical hemolytic-uremic syndrome.

What condition is associated with CFI p.Arg339Leu (c.1016G>T)?

CFI p.Arg339Leu (c.1016G>T) is associated with atypical hemolytic-uremic syndrome (ClinVar).

How common is CFI p.Arg339Leu (c.1016G>T) in the general population?

CFI p.Arg339Leu (c.1016G>T) is very rare (popmax 0.000424%, 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.Arg339Leu (c.1016G>T)?

AlphaMissense predicts likely pathogenic (score 0.9022) — an in-silico prediction, not a clinical call.

CFI p.Arg339Leu

c.1016G>T · rs773085612 · VCV1008106

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9022 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

atypical hemolytic-uremic syndrome

Computational evidence

Protein change
AlphaMissense	0.9022	likely pathogenic
REVEL	0.699	pathogenic-leaning
SaProt	LLR -10.17	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	Δ0.32	donor loss, 28 bp away · masked 0 · deltas
Pangolin	Δ0.26	loss · gain 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.5	GERP 1.6, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 61 kb · p 0.95 · regional, not allelic
Overall
CADD	24.2	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 0.000424% European (non-Finnish) · 5/1,179,576 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000342% 5/1,461,390 alleles · very rare

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.Arg339Leu
Coding: c.1016G>T
MANE Select: NM_000204
dbSNP: rs773085612
Type: single nucleotide variant
Location: chr4:109749527 (GRCh38)
Gene constraint: LOEUF 1.076 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.50 · 2 PDB
Residue 339: 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.Arg339Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
CFI p.Arg339Ter Conflicting classifications of pathogenicity ★ 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-arg339leu (accessed [today's date]).

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