Is CFP p.Arg159His (c.476G>A) pathogenic?

CFP p.Arg159His (c.476G>A) is classified Conflicting classifications of pathogenicity in CFP (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-04-09). AlphaMissense: likely benign (0.2357); Ultra-rare (popmax 0.0244%, mid); Associated with properdin deficiency, X-linked.

What condition is associated with CFP p.Arg159His (c.476G>A)?

CFP p.Arg159His (c.476G>A) is associated with properdin deficiency, X-linked (ClinVar).

How common is CFP p.Arg159His (c.476G>A) in the general population?

CFP p.Arg159His (c.476G>A) is ultra-rare (popmax 0.0244%, mid) (gnomAD).

How is Properdin deficiency inherited?

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

What do computational predictors say about CFP p.Arg159His (c.476G>A)?

AlphaMissense predicts likely benign (score 0.2357) — an in-silico prediction, not a clinical call.

CFP p.Arg159His

c.476G>A · rs200131215 · VCV973631

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.2357 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0244%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

properdin deficiency, X-linked

Computational evidence

Protein change
AlphaMissense	0.2357	likely benign
REVEL	0.679	pathogenic-leaning
SaProt	LLR -8.40	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.7	GERP 0.7, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 5,566 bp · p 3.9e-05 · regional, not allelic
Overall
CADD	20.7	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 0.0244% Middle Eastern · 1/4,097 alleles

Filtering AF 0.0114% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0106%

Overall 0.0115% 138/1,202,537 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0244%	4,097
South Asian	0.018%	5,551
European (non-Finnish)	0.0134%	7,491
Remaining individualsnot grpmax-eligible	0.0127%	7,877
Ashkenazi Jewishnot grpmax-eligible	0.00457%	21,875
African / African-American	0.00175%	57,076

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: CFP
Protein: p.Arg159His
Coding: c.476G>A
MANE Select: NM_001145252
dbSNP: rs200131215
Type: single nucleotide variant
Location: chrX:47627569 (GRCh38)
Structure: AlphaFold pLDDT 83.75 · 14 PDB
Residue 159: a disulfide bond; the tsp type-1 2 domain

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

Disease context

properdin deficiency, X-linked — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Properdin deficiency (Orphanet):

Inheritance: X-linked recessive

Similar variants

CFP p.Arg159Cys Uncertain significance ★★ ⚠ same residue
CFP p.Arg159= Likely benign ★ same residue
CFP p.Arg157Gln Uncertain significance ★★ ⚠ same condition
CFP p.Glu215Lys Uncertain significance ★★ ⚠ same condition
CFP p.Gly41Ser Benign/Likely benign ★★ ⚠ same condition
CFP c.767-2A>T Likely pathogenic ★ same condition
CFP p.Arg161Ter Pathogenic ★ same condition
CFP p.Ala242Ser 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/cfp-p-arg159his (accessed [today's date]).

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