Is CFI p.Ser268Leu (c.803C>T) pathogenic?

CFI p.Ser268Leu (c.803C>T) is classified Conflicting classifications of pathogenicity in CFI (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-09-26). AlphaMissense: ambiguous (0.5315); Ultra-rare (popmax 0.0165%, mid); Associated with CFI-related disorder.

What condition is associated with CFI p.Ser268Leu (c.803C>T)?

CFI p.Ser268Leu (c.803C>T) is associated with CFI-related disorder, complement factor I deficiency (ClinVar).

How common is CFI p.Ser268Leu (c.803C>T) in the general population?

CFI p.Ser268Leu (c.803C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about CFI p.Ser268Leu (c.803C>T)?

AlphaMissense predicts ambiguous (score 0.5315) — an in-silico prediction, not a clinical call.

CFI p.Ser268Leu

c.803C>T · rs2126213962 · VCV1687460

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.5315 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

CFI-related disorder

Computational evidence

Protein change
AlphaMissense	0.5315	ambiguous
REVEL	0.871	moderately pathogenic-leaning
SaProt	LLR -6.78	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.37 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 61 kb · p 0.95 · regional, not allelic
Overall
CADD	25.6	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 0.0165% Middle Eastern · 1/6,062 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000205% 3/1,461,644 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
European (non-Finnish)	0.00017%	589,915

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.Ser268Leu
Coding: c.803C>T
MANE Select: NM_000204
dbSNP: rs2126213962
Type: single nucleotide variant
Location: chr4:109760350 (GRCh38)
Gene constraint: LOEUF 1.076 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.50 · 2 PDB
Residue 268: a disulfide bond; the ldl-receptor class a 2 domain; a turn

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.Ser268= Benign/Likely benign ★★ 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
CFI p.Arg474Ter 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-ser268leu (accessed [today's date]).

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