Is CFD p.Ser42Ter (c.125C>A) pathogenic?

CFD p.Ser42Ter (c.125C>A) is classified Pathogenic in CFD (ClinVar, Single submitter, 4 submitters; last evaluated 2025-12-10). Very rare (popmax 0.00236%, sas); Associated with recurrent Neisseria infections due to factor D deficiency.

What condition is associated with CFD p.Ser42Ter (c.125C>A)?

CFD p.Ser42Ter (c.125C>A) is associated with recurrent Neisseria infections due to factor D deficiency (ClinVar).

How common is CFD p.Ser42Ter (c.125C>A) in the general population?

CFD p.Ser42Ter (c.125C>A) is very rare (popmax 0.00236%, sas) (gnomAD).

CFD p.Ser42Ter

Q: How is Recurrent Neisseria infections due to factor D deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.125C>A · rs104894667 · VCV16564

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 4 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00236%, sas)

Conditions

recurrent Neisseria infections due to factor D deficiency

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 2 of 5
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.6	GERP -1.4, phastCons 1
Overall
CADD	40.0	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 0.00236% South Asian · 2/84,658 alleles

Filtering AF 0.00125% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00106%

Overall 0.00169% 26/1,542,878 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00236%	42,329
Admixed American	0.00191%	52,416
European (non-Finnish)	0.00191%	52,484
Remaining individualsnot grpmax-eligible	0.00167%	60,008

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: CFD
Protein: p.Ser42Ter
Coding: c.125C>A
MANE Select: NM_001928
dbSNP: rs104894667
Type: single nucleotide variant
Location: chr19:860686 (GRCh38)
Gene constraint: LOEUF 1.948 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 91.19 · 40 PDB
Residue 42: the peptidase s1 domain; a β-strand

Full CFD gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

recurrent Neisseria infections due to factor D deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Recurrent Neisseria infections due to factor D deficiency (Orphanet):

Inheritance: Autosomal recessive

Similar variants

CFD p.Ser42Trp Uncertain significance ★ ⚠ same residue
CFD p.Ser42= Likely benign ★ same residue
CFD c.212+2T>G Likely pathogenic ★★ same condition
CFD c.56-1G>C Likely pathogenic ★★ same condition
CFD p.Tyr95Ter Pathogenic ★★ same condition
CFD c.213-1G>C Likely pathogenic ★ same condition
CFD p.Gly216Ser Uncertain significance ★ ⚠ same condition
CFD p.Gly52Asp 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/cfd-p-ser42ter (accessed [today's date]).

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