Is CFTR p.Pro140Arg (c.419C>G) pathogenic?

CFTR p.Pro140Arg (c.419C>G) is classified Uncertain significance in CFTR (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-08). AlphaMissense: ambiguous (0.4542); Very rare (popmax 0.000254%, nfe); Associated with cystic fibrosis.

What condition is associated with CFTR p.Pro140Arg (c.419C>G)?

CFTR p.Pro140Arg (c.419C>G) is associated with cystic fibrosis (ClinVar).

How common is CFTR p.Pro140Arg (c.419C>G) in the general population?

CFTR p.Pro140Arg (c.419C>G) is very rare (popmax 0.000254%, nfe) (gnomAD).

How is Cystic fibrosis inherited?

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

What do computational predictors say about CFTR p.Pro140Arg (c.419C>G)?

AlphaMissense predicts ambiguous (score 0.4542) — an in-silico prediction, not a clinical call.

CFTR p.Pro140Arg

c.419C>G · rs397508694 · VCV2918673

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4542 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

cystic fibrosis

Computational evidence

Protein change
AlphaMissense	0.4542	ambiguous
REVEL	0.833	moderately pathogenic-leaning
SaProt	LLR -9.79	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.1, phastCons 1
Regional constraint	o/e 1.13	unconstrained · MANE · 187 kb · p 2.1e-08 · regional, not allelic
Overall
CADD	24.6	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 0.000254% European (non-Finnish) · 3/1,179,866 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000205% 3/1,461,498 alleles · very rare

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: CFTR
Protein: p.Pro140Arg
Coding: c.419C>G
MANE Select: NM_000492
dbSNP: rs397508694
Type: single nucleotide variant
Location: chr7:117531044 (GRCh38)
Gene constraint: LOEUF 1.152 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 75.96 · 60 PDB
Residue 140: the abc transmembrane type-1 1 domain; an α-helix

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

Disease context

cystic fibrosis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Cystic fibrosis (Orphanet):

Inheritance: Autosomal recessive
Onset: All ages
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

CFTR p.Pro140Ala Uncertain significance ★★ ⚠ same residue
CFTR p.Pro140Ser Uncertain significance ★★ ⚠ same residue
CFTR p.Pro140Leu Uncertain significance ★ ⚠ same residue
CFTR p.Pro140= Likely benign ★ same residue
CFTR c.1585-1G>A Pathogenic ★★★★ same condition
CFTR c.1766+1G>A Pathogenic ★★★★ same condition
CFTR c.2657+5G>A Pathogenic ★★★★ same condition
CFTR c.2988+1G>A Pathogenic ★★★★ 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/cftr-p-pro140arg (accessed [today's date]).

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