Is CFP p.Arg222Cys (c.664C>T) pathogenic?

CFP p.Arg222Cys (c.664C>T) is classified Uncertain significance in CFP (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-26). AlphaMissense: likely pathogenic (0.7507); Very rare (popmax 0.00435%, amr).

How common is CFP p.Arg222Cys (c.664C>T) in the general population?

CFP p.Arg222Cys (c.664C>T) is very rare (popmax 0.00435%, amr) (gnomAD).

What do computational predictors say about CFP p.Arg222Cys (c.664C>T)?

AlphaMissense predicts likely pathogenic (score 0.7507) — an in-silico prediction, not a clinical call.

CFP p.Arg222Cys

c.664C>T · rs1444150137 · VCV2878630

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7507 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00435%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.7507	likely pathogenic
REVEL	0.371	indeterminate
SaProt	LLR -13.48	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.3	GERP 0.51, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 5,566 bp · p 3.9e-05 · regional, not allelic
Overall
CADD	24.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00435% Admixed American · 2/45,946 alleles

Filtering AF 0.000722% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00027%

Overall 0.000331% 4/1,210,017 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00435%	22,973
African / African-American	0.00174%	57,425
European (non-Finnish)	0.000112%	894,863

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.Arg222Cys
Coding: c.664C>T
MANE Select: NM_001145252
dbSNP: rs1444150137
Type: single nucleotide variant
Location: chrX:47627243 (GRCh38)
Structure: AlphaFold pLDDT 83.75 · 14 PDB
Residue 222: a disulfide bond; the tsp type-1 3 domain; the 'disordered' region

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

Similar variants

CFP p.Arg222His Uncertain significance ★ ⚠ same residue
CFP p.Trp321Gly Pathogenic ★★ same type
CFP p.Ala402Gly Uncertain significance ★★ ⚠ same type
CFP p.Arg157Gln Uncertain significance ★★ ⚠ same type
CFP p.Arg157Trp Uncertain significance ★★ ⚠ same type
CFP p.Arg159Cys Uncertain significance ★★ ⚠ same type
CFP p.Arg247Trp Uncertain significance ★★ ⚠ same type
CFP p.Arg438Trp Uncertain significance ★★ ⚠ same type

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-arg222cys (accessed [today's date]).

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