Is CFTR p.Pro499Ala (c.1495C>G) pathogenic?

CFTR p.Pro499Ala (c.1495C>G) is classified Uncertain significance in CFTR (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-01-26). AlphaMissense: likely benign (0.2441); Very rare (popmax 0.00167%, amr); Associated with cystic fibrosis.

What condition is associated with CFTR p.Pro499Ala (c.1495C>G)?

CFTR p.Pro499Ala (c.1495C>G) is associated with cystic fibrosis (ClinVar).

How common is CFTR p.Pro499Ala (c.1495C>G) in the general population?

CFTR p.Pro499Ala (c.1495C>G) is very rare (popmax 0.00167%, amr) (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.Pro499Ala (c.1495C>G)?

AlphaMissense predicts likely benign (score 0.2441) — an in-silico prediction, not a clinical call.

CFTR p.Pro499Ala

c.1495C>G · rs397508219 · VCV53268

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.2441 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cystic fibrosis

Computational evidence

Protein change
AlphaMissense	0.2441	likely benign
REVEL	0.838	moderately pathogenic-leaning
SaProt	LLR -5.65	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.7, phastCons 1
Regional constraint	o/e 1.13	unconstrained · MANE · 187 kb · p 2.1e-08 · regional, not allelic
Overall
CADD	25.3	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 0.00167% Admixed American · 1/59,992 alleles

Filtering AF 0.000501% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000366%

Overall 0.000745% 12/1,611,738 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,992
European (non-Finnish)	0.000934%	107,110

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.Pro499Ala
Coding: c.1495C>G
MANE Select: NM_000492
dbSNP: rs397508219
Type: single nucleotide variant
Location: chr7:117559566 (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 499: a UniProt-annotated variant site (in cf); the abc transporter 1 domain; a β-strand

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.Pro499Leu Uncertain significance ★ ⚠ same residue
CFTR p.Pro499= Likely benign ★ same residue
CFTR p.Pro499Thr 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
CFTR c.2988+1G>A Pathogenic ★★★★ same condition
CFTR c.3718-2477C>T 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-pro499ala (accessed [today's date]).

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