Is CFTR p.Pro477Ser (c.1429C>T) pathogenic?

CFTR p.Pro477Ser (c.1429C>T) is classified Uncertain significance in CFTR (ClinVar, Multiple submitters, 8 submitters; last evaluated 2025-12-17). AlphaMissense: ambiguous (0.3522); Ultra-rare (popmax 0.0212%, nfe); Associated with cystic fibrosis.

What condition is associated with CFTR p.Pro477Ser (c.1429C>T)?

CFTR p.Pro477Ser (c.1429C>T) is associated with cystic fibrosis (ClinVar).

How common is CFTR p.Pro477Ser (c.1429C>T) in the general population?

CFTR p.Pro477Ser (c.1429C>T) is ultra-rare (popmax 0.0212%, 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.Pro477Ser (c.1429C>T)?

AlphaMissense predicts ambiguous (score 0.3522) — an in-silico prediction, not a clinical call.

CFTR p.Pro477Ser

c.1429C>T · rs139054556 · VCV455762

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

ambiguous

0.3522 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0212%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

cystic fibrosis

Computational evidence

Protein change
AlphaMissense	0.3522	ambiguous
REVEL	0.723	pathogenic-leaning
SaProt	LLR -9.64	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 4.4	GERP 1.7, phastCons 1
Regional constraint	o/e 1.13	unconstrained · MANE · 187 kb · p 2.1e-08 · regional, not allelic
Overall
CADD	23.5	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 0.0212% European (non-Finnish) · 250/1,177,436 alleles

Filtering AF 0.019% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0182%

Overall 0.0161% 259/1,610,844 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0212%	4,710
Remaining individualsnot grpmax-eligible	0.00641%	15,597
African / African-American	0.00535%	18,686
Admixed American	0.00167%	59,972

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.Pro477Ser
Coding: c.1429C>T
MANE Select: NM_000492
dbSNP: rs139054556
Type: single nucleotide variant
Location: chr7:117559500 (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 477: 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

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.Pro477His Uncertain significance ★★ ⚠ same residue
CFTR p.Pro477Leu Uncertain significance ★★ ⚠ same residue
CFTR p.Pro477Ala Uncertain significance ★ ⚠ same residue
CFTR p.Pro477= Likely benign ★ same residue
CFTR p.Pro477Thr Uncertain significance ★ ⚠ 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

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-pro477ser (accessed [today's date]).

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