Is CFI p.Ser268= (c.804G>A) pathogenic?

CFI p.Ser268= (c.804G>A) is classified Benign/Likely benign in CFI (ClinVar, Multiple submitters, 11 submitters; last evaluated 2026-02-04). Common (popmax 42%, amr) — too common for a highly-penetrant pathogenic allele; Associated with CFI-related disorder.

What condition is associated with CFI p.Ser268= (c.804G>A)?

CFI p.Ser268= (c.804G>A) is associated with CFI-related disorder, complement factor I deficiency, atypical hemolytic-uremic syndrome with I factor anomaly (ClinVar).

CFI p.Ser268=

Q: How common is CFI p.Ser268= (c.804G>A) in the general population?

CFI p.Ser268= (c.804G>A) is common (popmax 42%, amr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.804G>A · rs2298749 · VCV347167

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 11 submitters

gnomAD v4.1

Common

common (popmax 42%, amr) — too common for a highly-penetrant pathogenic allele

Conditions

CFI-related disorder

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 -20	GERP -3.5
Overall
CADD	0.047	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 42% Admixed American · 25,217/59,996 alleles

Filtering AF 41.6% ClinGen BA1/BS1 input FAF95, joint · FAF99 41.4%

Overall 26.7% 430,920/1,612,514 alleles · common

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	43.9%	2
Admixed Americangrpmax	42%	2
African / African-American	36.7%	3
Middle Eastern	34.2%	3
East Asian	33.2%	3
Ashkenazi Jewishnot grpmax-eligible	30.2%	3
Finnishnot grpmax-eligible	29.7%	3
Remaining individualsnot grpmax-eligible	28.7%	3
European (non-Finnish)	24.9%	4
South Asian	23.6%	4

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ser268=
Coding: c.804G>A
MANE Select: NM_000204
dbSNP: rs2298749
Type: single nucleotide variant
Location: chr4:109760349 (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 atypical hemolytic-uremic syndrome with I factor anomaly

Similar variants

CFI p.Ser268Leu 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
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-ser268 (accessed [today's date]).

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