Is CFP p.Arg222His (c.665G>A) pathogenic?

CFP p.Arg222His (c.665G>A) is classified Uncertain significance in CFP (ClinVar, Single submitter, 2 submitters; last evaluated 2025-12-15). AlphaMissense: ambiguous (0.3932); Ultra-rare (popmax 0.0588%, amr).

How common is CFP p.Arg222His (c.665G>A) in the general population?

CFP p.Arg222His (c.665G>A) is ultra-rare (popmax 0.0588%, amr) (gnomAD).

What do computational predictors say about CFP p.Arg222His (c.665G>A)?

AlphaMissense predicts ambiguous (score 0.3932) — an in-silico prediction, not a clinical call.

CFP p.Arg222His

c.665G>A · rs185246758 · VCV1381377

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3932 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0588%, amr)

Computational evidence

Protein change
AlphaMissense	0.3932	ambiguous
REVEL	0.437	indeterminate
SaProt	LLR -12.03	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP 1.6, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 5,566 bp · p 3.9e-05 · regional, not allelic
Overall
CADD	24.4	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 0.0588% Admixed American · 27/45,946 alleles

Filtering AF 0.0414% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0356%

Overall 0.00703% 85/1,209,944 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0588%	1,702
Remaining individualsnot grpmax-eligible	0.0336%	2,973
African / African-American	0.0122%	8,212
European (non-Finnish)	0.0038%	26,317
South Asian	0.00176%	56,682

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.Arg222His
Coding: c.665G>A
MANE Select: NM_001145252
dbSNP: rs185246758
Type: single nucleotide variant
Location: chrX:47627242 (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.Arg222Cys 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-arg222his (accessed [today's date]).

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