Is CFTR p.Pro439Arg (c.1316C>G) pathogenic?

CFTR p.Pro439Arg (c.1316C>G) is classified Uncertain significance in CFTR (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-19). AlphaMissense: likely benign (0.2175); Absent from gnomAD v4.1.

How common is CFTR p.Pro439Arg (c.1316C>G) in the general population?

CFTR p.Pro439Arg (c.1316C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CFTR p.Pro439Arg (c.1316C>G)?

AlphaMissense predicts likely benign (score 0.2175) — an in-silico prediction, not a clinical call.

CFTR p.Pro439Arg

c.1316C>G · VCV3339495

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2175 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2175	likely benign
REVEL	0.824	moderately pathogenic-leaning
SaProt	LLR -10.46	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP 0.47, phastCons 1
Regional constraint	o/e 1.13	unconstrained · MANE · 187 kb · p 2.1e-08 · regional, not allelic
Overall
CADD	25.2	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CFTR
Protein: p.Pro439Arg
Coding: c.1316C>G
MANE Select: NM_000492
Type: single nucleotide variant
Location: chr7:117548747 (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 439: a UniProt-annotated variant site (in cf); the abc transporter 1 domain

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

Similar variants

CFTR p.Pro439Thr Uncertain significance ★★ ⚠ same residue
CFTR p.Pro439= Likely benign ★★ same residue
CFTR p.Pro439Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
CFTR c.1585-1G>A Pathogenic ★★★★ same type
CFTR c.1766+1G>A Pathogenic ★★★★ same type
CFTR c.2657+5G>A Pathogenic ★★★★ same type
CFTR c.2988+1G>A Pathogenic ★★★★ same type
CFTR c.3718-2477C>T Pathogenic ★★★★ 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/cftr-p-pro439arg (accessed [today's date]).

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