Is CFTR p.Val520Phe (c.1558G>T) pathogenic?

CFTR p.Val520Phe (c.1558G>T) is classified Pathogenic in CFTR (ClinVar, Expert panel, 14 submitters; last evaluated 2017-03-17). AlphaMissense: likely pathogenic (0.8789); Very rare (popmax 0.00331%, nfe); Associated with cystic fibrosis.

How common is CFTR p.Val520Phe (c.1558G>T) in the general population?

CFTR p.Val520Phe (c.1558G>T) is very rare (popmax 0.00331%, nfe) (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.Val520Phe (c.1558G>T)?

AlphaMissense predicts likely pathogenic (score 0.8789) — an in-silico prediction, not a clinical call.

CFTR p.Val520Phe

Q: What condition is associated with CFTR p.Val520Phe (c.1558G>T)?

CFTR p.Val520Phe (c.1558G>T) is associated with cystic fibrosis, bronchiectasis with or without elevated sweat chloride 1, congenital bilateral aplasia of vas deferens from CFTR mutation (ClinVar).

c.1558G>T · rs77646904 · VCV7150

Pathogenic Expert panel

Classification

Pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 14 submitters

AlphaMissense

likely pathogenic

0.8789 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00331%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cystic fibrosis

Computational evidence

Protein change
AlphaMissense	0.8789	likely pathogenic ✓ concordant with ClinVar
REVEL	0.871	moderately pathogenic-leaning
SaProt	LLR -15.62	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP 1.7, phastCons 1
Regional constraint	o/e 1.13	unconstrained · MANE · 187 kb · p 2.1e-08 · regional, not allelic
Overall
CADD	24.1	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 0.00331% European (non-Finnish) · 39/1,179,464 alleles

Filtering AF 0.00247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00217%

Overall 0.00267% 43/1,613,014 alleles · very rare exomes 42/1,460,978 · genomes 1/152,036 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0048%	20,818
European (non-Finnish)grpmax	0.00331%	30,243
African / African-American	0.00134%	74,852

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Val520Phe
Coding: c.1558G>T
MANE Select: NM_000492
dbSNP: rs77646904
Type: single nucleotide variant
Location: chr7:117559629 (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 520: a UniProt-annotated variant site (in cf); 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

Also linked: bronchiectasis with or without elevated sweat chloride 1 congenital bilateral aplasia of vas deferens from CFTR mutation CFTR-related disorder

For Cystic fibrosis (Orphanet):

Inheritance: Autosomal recessive
Onset: All ages
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

CFTR p.Val520= Likely benign ★★ same residue
CFTR p.Val520Asp Likely pathogenic ★ same residue
CFTR p.Val520Ile Conflicting classifications of pathogenicity ★ ⚠ same residue
CFTR p.Val520Ala Likely pathogenic same residue
CFTR p.Val520Leu Likely 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

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-val520phe (accessed [today's date]).

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