Is CFTR p.Ser753= (c.2259C>T) pathogenic?

CFTR p.Ser753= (c.2259C>T) is classified Conflicting classifications of pathogenicity in CFTR (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2024-01-05). Ultra-rare (popmax 0.033%, mid); Associated with CFTR-related disorder.

What condition is associated with CFTR p.Ser753= (c.2259C>T)?

CFTR p.Ser753= (c.2259C>T) is associated with CFTR-related disorder, cystic fibrosis (ClinVar).

How common is CFTR p.Ser753= (c.2259C>T) in the general population?

CFTR p.Ser753= (c.2259C>T) is ultra-rare (popmax 0.033%, mid) (gnomAD).

CFTR p.Ser753=

c.2259C>T · rs201888075 · VCV53464

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.033%, mid)

Conditions

CFTR-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -6.6	GERP -3.3
Overall
CADD	0.273	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.033% Middle Eastern · 2/6,068 alleles

Filtering AF 0.00581% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00242%

Overall 0.00298% 48/1,611,884 alleles · ultra-rare exomes 45/1,459,694 · genomes 3/152,190 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.033%	3,034
Remaining individualsnot grpmax-eligible	0.0144%	6,931
Finnishnot grpmax-eligible	0.00313%	31,984
European (non-Finnish)	0.00288%	34,673
South Asian	0.0011%	90,722

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.Ser753=
Coding: c.2259C>T
MANE Select: NM_000492
dbSNP: rs201888075
Type: single nucleotide variant
Location: chr7:117592426 (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 753: a UniProt-annotated variant site (in cf); the 'disordered r region' region; an α-helix; a modified residue (phosphoserine; by pka)

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

Disease context

Also linked: cystic fibrosis

Similar variants

CFTR p.Ser753Cys Uncertain significance ★ ⚠ same residue
CFTR p.Ser753Gly 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
CFTR c.489+1G>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-ser753 (accessed [today's date]).

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