Is CFP p.Arg346Cys (c.1036C>T) pathogenic?

CFP p.Arg346Cys (c.1036C>T) is classified Uncertain significance in CFP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-17). AlphaMissense: likely pathogenic (0.7759); Ultra-rare (popmax 0.0689%, mid).

How common is CFP p.Arg346Cys (c.1036C>T) in the general population?

CFP p.Arg346Cys (c.1036C>T) is ultra-rare (popmax 0.0689%, mid) (gnomAD).

What do computational predictors say about CFP p.Arg346Cys (c.1036C>T)?

AlphaMissense predicts likely pathogenic (score 0.7759) — an in-silico prediction, not a clinical call.

CFP p.Arg346Cys

c.1036C>T · VCV3724229

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7759 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0689%, mid)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7759	likely pathogenic
REVEL	0.808	moderately pathogenic-leaning
SaProt	LLR -13.79	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 5,566 bp · p 3.9e-05 · regional, not allelic
Overall
CADD	26.2	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 0.0689% Middle Eastern · 3/4,356 alleles

Filtering AF 0.0187% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00995%

Overall 0.000546% 6/1,098,086 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0689%	1,452
European (non-Finnish)	0.000335%	298,474

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.Arg346Cys
Coding: c.1036C>T
MANE Select: NM_001145252
Type: single nucleotide variant
Location: chrX:47626424 (GRCh38)
Structure: AlphaFold pLDDT 83.75 · 14 PDB
Residue 346: a β-strand; a disulfide bond; the tsp type-1 5 domain

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

Similar variants

CFP p.Arg346= Likely benign ★ 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-arg346cys (accessed [today's date]).

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