Is CFI p.Arg339Ter (c.1015C>T) pathogenic?

CFI p.Arg339Ter (c.1015C>T) is classified Conflicting classifications of pathogenicity in CFI (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-09-26). Ultra-rare (popmax 0.011%, sas); Associated with CFI-related disorder.

What condition is associated with CFI p.Arg339Ter (c.1015C>T)?

CFI p.Arg339Ter (c.1015C>T) is associated with CFI-related disorder, complement factor I deficiency (ClinVar).

How common is CFI p.Arg339Ter (c.1015C>T) in the general population?

CFI p.Arg339Ter (c.1015C>T) is ultra-rare (popmax 0.011%, sas) (gnomAD).

CFI p.Arg339Ter

c.1015C>T · rs762761680 · VCV1319494

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.011%, sas)

Conditions

CFI-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 9 of 13
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.44	loss · gain 0.00 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 3.4	GERP -1.8, phastCons 1
Overall
CADD	35.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.011% South Asian · 10/91,054 alleles

Filtering AF 0.00594% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00453%

Overall 0.00167% 27/1,613,392 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.011%	9,105
East Asian	0.00446%	22,436
European (non-Finnish)	0.00127%	78,632

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.Arg339Ter
Coding: c.1015C>T
MANE Select: NM_000204
dbSNP: rs762761680
Type: single nucleotide variant
Location: chr4:109749528 (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

Also linked: complement factor I deficiency

Similar variants

CFI p.Arg339Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
CFI p.Arg339Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
CFI c.1429+1G>C Pathogenic/Likely pathogenic ★★ same condition
CFI c.57+1G>C Likely pathogenic ★★ same condition
CFI c.658+1G>A 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

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-arg339ter (accessed [today's date]).

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