Is CFP p.Pro454Ala (c.1360C>G) pathogenic?

CFP p.Pro454Ala (c.1360C>G) is classified Conflicting classifications of pathogenicity in CFP (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-06-22). AlphaMissense: likely benign (0.0792); Rare (popmax 0.667%, mid); Associated with CFP-related disorder.

What condition is associated with CFP p.Pro454Ala (c.1360C>G)?

CFP p.Pro454Ala (c.1360C>G) is associated with CFP-related disorder (ClinVar).

How common is CFP p.Pro454Ala (c.1360C>G) in the general population?

CFP p.Pro454Ala (c.1360C>G) is rare (popmax 0.667%, mid) (gnomAD).

What do computational predictors say about CFP p.Pro454Ala (c.1360C>G)?

AlphaMissense predicts likely benign (score 0.0792) — an in-silico prediction, not a clinical call.

CFP p.Pro454Ala

c.1360C>G · rs768994510 · VCV1497624

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0792 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.667%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

CFP-related disorder

Computational evidence

Protein change
AlphaMissense	0.0792	likely benign
REVEL	0.059	moderately benign-leaning
SaProt	LLR -7.63	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.6	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	22.4	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 0.667% Middle Eastern · 29/4,350 alleles

Filtering AF 0.477% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.413%

Overall 0.00331% 40/1,207,908 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.667%	150
Remaining individualsnot grpmax-eligible	0.0063%	15,861
European (non-Finnish)	0.000894%	111,831

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.Pro454Ala
Coding: c.1360C>G
MANE Select: NM_001145252
dbSNP: rs768994510
Type: single nucleotide variant
Location: chrX:47624325 (GRCh38)
Structure: AlphaFold pLDDT 83.75 · 14 PDB
Residue 454: a β-strand; a disulfide bond; the tsp type-1 6 domain

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

Disease context

CFP-related disorder

Similar variants

CFP p.Pro454Ser Uncertain significance ★★ ⚠ same residue
CFP p.Trp107Ter Likely pathogenic ★ same condition
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

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-pro454ala (accessed [today's date]).

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