Is CFTR p.Ser737Phe (c.2210C>T) pathogenic?

CFTR p.Ser737Phe (c.2210C>T) is classified Conflicting classifications of pathogenicity in CFTR (ClinVar, Conflicting submitters, 9 submitters; last evaluated 2025-12-10). AlphaMissense: likely benign (0.3079); Very rare (popmax 0.00119%, nfe); Associated with CFTR-related disorder.

What condition is associated with CFTR p.Ser737Phe (c.2210C>T)?

CFTR p.Ser737Phe (c.2210C>T) is associated with CFTR-related disorder, bronchiectasis with or without elevated sweat chloride 1, cystic fibrosis (ClinVar).

How common is CFTR p.Ser737Phe (c.2210C>T) in the general population?

CFTR p.Ser737Phe (c.2210C>T) is very rare (popmax 0.00119%, nfe) (gnomAD).

What do computational predictors say about CFTR p.Ser737Phe (c.2210C>T)?

AlphaMissense predicts likely benign (score 0.3079) — an in-silico prediction, not a clinical call.

CFTR p.Ser737Phe

c.2210C>T · rs186089140 · VCV53454

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.3079 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00119%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

CFTR-related disorder

Computational evidence

Protein change
AlphaMissense	0.3079	likely benign
REVEL	0.882	moderately pathogenic-leaning
SaProt	LLR -11.67	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 7.6	GERP 1.8, phastCons 1
Regional constraint	o/e 1.13	unconstrained · MANE · 187 kb · p 2.1e-08 · regional, not allelic
Overall
CADD	25.8	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 0.00119% European (non-Finnish) · 14/1,179,994 alleles

Filtering AF 0.000688% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000539%

Overall 0.000867% 14/1,614,100 alleles · very rare

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.Ser737Phe
Coding: c.2210C>T
MANE Select: NM_000492
dbSNP: rs186089140
Type: single nucleotide variant
Location: chr7:117592377 (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 737: a UniProt-annotated variant site (in cf); the 'disordered r region' region; a modified residue (phosphoserine; by pka)

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

Disease context

Also linked: bronchiectasis with or without elevated sweat chloride 1 cystic fibrosis

Similar variants

CFTR p.Ser737= Likely benign ★★ 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
CFTR c.579+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-ser737phe (accessed [today's date]).

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