Is CFTR p.Ala559Ser (c.1675G>T) pathogenic?

CFTR p.Ala559Ser (c.1675G>T) is classified Uncertain significance in CFTR (ClinVar, Single submitter, 1 submitter; last evaluated 2019-07-31). AlphaMissense: ambiguous (0.4233); Absent from gnomAD v4.1; Associated with cystic fibrosis.

What condition is associated with CFTR p.Ala559Ser (c.1675G>T)?

CFTR p.Ala559Ser (c.1675G>T) is associated with cystic fibrosis (ClinVar).

How common is CFTR p.Ala559Ser (c.1675G>T) in the general population?

CFTR p.Ala559Ser (c.1675G>T) is absent from gnomAD v4.1 (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.Ala559Ser (c.1675G>T)?

AlphaMissense predicts ambiguous (score 0.4233) — an in-silico prediction, not a clinical call.

CFTR p.Ala559Ser

c.1675G>T · rs75549581 · VCV955475

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4233 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,576,230)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

cystic fibrosis

Computational evidence

Protein change
AlphaMissense	0.4233	ambiguous
REVEL	0.919	moderately pathogenic-leaning
SaProt	LLR -12.40	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.5, phastCons 1
Regional constraint	o/e 1.13	unconstrained · MANE · 187 kb · p 2.1e-08 · regional, not allelic
Overall
CADD	26.9	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

No allele count reported in gnomAD v4.1 (AN 1,576,230). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: CFTR
Protein: p.Ala559Ser
Coding: c.1675G>T
MANE Select: NM_000492
dbSNP: rs75549581
Type: single nucleotide variant
Location: chr7:117587829 (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 559: a UniProt-annotated variant site (in cf); a UniProt-annotated variant site (in cf; impaired maturation of glycan chains); the abc transporter 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.Ala559Thr Pathogenic ★★★ same residue
CFTR p.Ala559Pro Pathogenic/Likely pathogenic ★★ same residue
CFTR p.Ala559fs Pathogenic ★ 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-ala559ser (accessed [today's date]).

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