Is CFTR p.Tyr577Phe (c.1730A>T) pathogenic?

CFTR p.Tyr577Phe (c.1730A>T) is classified Conflicting classifications of pathogenicity in CFTR (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2024-09-17). AlphaMissense: likely benign (0.1003); Very rare (popmax 0.0011%, sas); Associated with cystic fibrosis.

What condition is associated with CFTR p.Tyr577Phe (c.1730A>T)?

CFTR p.Tyr577Phe (c.1730A>T) is associated with cystic fibrosis (ClinVar).

How common is CFTR p.Tyr577Phe (c.1730A>T) in the general population?

CFTR p.Tyr577Phe (c.1730A>T) is very rare (popmax 0.0011%, sas) (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.Tyr577Phe (c.1730A>T)?

AlphaMissense predicts likely benign (score 0.1003) — an in-silico prediction, not a clinical call.

CFTR p.Tyr577Phe

c.1730A>T · rs397508286 · VCV53362

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.1003 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cystic fibrosis

Computational evidence

Protein change
AlphaMissense	0.1003	likely benign
REVEL	0.67	pathogenic-leaning
SaProt	LLR -5.97	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	Δ0.28	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 9.3	GERP 1.5, phastCons 1
Regional constraint	o/e 1.13	unconstrained · MANE · 187 kb · p 2.1e-08 · regional, not allelic
Overall
CADD	25.9	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

Grpmax group 0.0011% South Asian · 1/90,934 alleles

Overall 6.24e-05% 1/1,603,396 alleles · very rare exomes 1/1,451,204 · genomes 0/152,192 · 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.Tyr577Phe
Coding: c.1730A>T
MANE Select: NM_000492
dbSNP: rs397508286
Type: single nucleotide variant
Location: chr7:117590403 (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 577: a UniProt-annotated variant site (in cf); the abc transporter 1 domain; a turn

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.Tyr577= Conflicting classifications of pathogenicity ★ same residue
CFTR p.Tyr577Ter 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
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-tyr577phe (accessed [today's date]).

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