Is CFTR p.Phe693Ser (c.2078T>C) pathogenic?

CFTR p.Phe693Ser (c.2078T>C) is classified Uncertain significance in CFTR (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-08). AlphaMissense: likely benign (0.0909); Very rare (popmax 0.00133%, afr); Associated with cystic fibrosis.

What condition is associated with CFTR p.Phe693Ser (c.2078T>C)?

CFTR p.Phe693Ser (c.2078T>C) is associated with cystic fibrosis (ClinVar).

How common is CFTR p.Phe693Ser (c.2078T>C) in the general population?

CFTR p.Phe693Ser (c.2078T>C) is very rare (popmax 0.00133%, afr) (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.Phe693Ser (c.2078T>C)?

AlphaMissense predicts likely benign (score 0.0909) — an in-silico prediction, not a clinical call.

CFTR p.Phe693Ser

c.2078T>C · VCV4227389

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0909 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

cystic fibrosis

Computational evidence

Protein change
AlphaMissense	0.0909	likely benign
REVEL	0.535	indeterminate
SaProt	LLR -4.53	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3	GERP 1.7, phastCons 1
Regional constraint	o/e 1.13	unconstrained · MANE · 187 kb · p 2.1e-08 · regional, not allelic
Overall
CADD	22.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/74,908 alleles

Overall 6.2e-05% 1/1,613,672 alleles · very rare exomes 0/1,461,562 · genomes 1/152,110 · joint denominator

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.Phe693Ser
Coding: c.2078T>C
MANE Select: NM_000492
Type: single nucleotide variant
Location: chr7:117592245 (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 693: a UniProt-annotated variant site (in cf); a UniProt-annotated variant site (in cf; uncertain significance; no effect on glycan maturation; no effect on channel activity and); the 'disordered r region' region

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.Phe693Ile Uncertain significance ★ ⚠ same residue
CFTR p.Phe693Leu Conflicting classifications of pathogenicity ★ 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-phe693ser (accessed [today's date]).

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