Is CFTR p.Ser42Phe (c.125C>T) pathogenic?

CFTR p.Ser42Phe (c.125C>T) is classified Conflicting classifications of pathogenicity in CFTR (ClinVar, Conflicting submitters, 18 submitters; last evaluated 2026-03-27). AlphaMissense: likely benign (0.1165); Ultra-rare (popmax 0.017%, nfe); Associated with CFTR-related disorder.

What condition is associated with CFTR p.Ser42Phe (c.125C>T)?

CFTR p.Ser42Phe (c.125C>T) is associated with CFTR-related disorder, hereditary chronic pancreatitis, bronchiectasis with or without elevated sweat chloride 1 (ClinVar).

How common is CFTR p.Ser42Phe (c.125C>T) in the general population?

CFTR p.Ser42Phe (c.125C>T) is ultra-rare (popmax 0.017%, nfe) (gnomAD).

What do computational predictors say about CFTR p.Ser42Phe (c.125C>T)?

AlphaMissense predicts likely benign (score 0.1165) — an in-silico prediction, not a clinical call.

CFTR p.Ser42Phe

c.125C>T · rs143456784 · VCV35819

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 18 submitters

AlphaMissense

likely benign

0.1165 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.017%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

CFTR-related disorder

Computational evidence

Protein change
AlphaMissense	0.1165	likely benign
REVEL	0.714	pathogenic-leaning
SaProt	LLR -7.60	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.4, phastCons 1
Regional constraint	o/e 1.13	unconstrained · MANE · 187 kb · p 2.1e-08 · regional, not allelic
Overall
CADD	24.7	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 0.017% European (non-Finnish) · 200/1,175,522 alleles

Filtering AF 0.0151% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0143%

Overall 0.0129% 207/1,608,896 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.017%	5,878
Remaining individualsnot grpmax-eligible	0.00482%	20,765
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,554
Admixed American	0.00167%	59,972
African / African-American	0.00134%	74,786
South Asian	0.0011%	90,968

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.Ser42Phe
Coding: c.125C>T
MANE Select: NM_000492
dbSNP: rs143456784
Type: single nucleotide variant
Location: chr7:117504324 (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 42: an α-helix; a UniProt-annotated variant site (in cf)

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

Disease context

Also linked: hereditary chronic pancreatitis bronchiectasis with or without elevated sweat chloride 1 cystic fibrosis congenital bilateral aplasia of vas deferens from CFTR mutation

Similar variants

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CFTR c.3718-2477C>T Pathogenic ★★★★ same condition
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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-ser42phe (accessed [today's date]).

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