Is CFTR p.Pro41Arg (c.122C>G) pathogenic?

CFTR p.Pro41Arg (c.122C>G) is classified Uncertain significance in CFTR (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-29). AlphaMissense: likely benign (0.1927); Very rare (popmax 0.0011%, sas); Associated with cystic fibrosis.

What condition is associated with CFTR p.Pro41Arg (c.122C>G)?

CFTR p.Pro41Arg (c.122C>G) is associated with cystic fibrosis (ClinVar).

How common is CFTR p.Pro41Arg (c.122C>G) in the general population?

CFTR p.Pro41Arg (c.122C>G) 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.Pro41Arg (c.122C>G)?

AlphaMissense predicts likely benign (score 0.1927) — an in-silico prediction, not a clinical call.

CFTR p.Pro41Arg

c.122C>G · rs2484968302 · VCV2567869

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1927 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

cystic fibrosis

Computational evidence

Protein change
AlphaMissense	0.1927	likely benign
REVEL	0.403	indeterminate
SaProt	LLR -9.09	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 4.1	GERP 1.4, phastCons 1
Regional constraint	o/e 1.13	unconstrained · MANE · 187 kb · p 2.1e-08 · regional, not allelic
Overall
CADD	24.0	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 0.0011% South Asian · 1/91,014 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000274% 4/1,458,930 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,014
European (non-Finnish)	0.000255%	392,494

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.Pro41Arg
Coding: c.122C>G
MANE Select: NM_000492
dbSNP: rs2484968302
Type: single nucleotide variant
Location: chr7:117504321 (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 41: 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

For Cystic fibrosis (Orphanet):

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

Similar variants

CFTR p.Pro41= Likely benign ★★ same residue
CFTR p.Pro41Ala Uncertain significance ★ ⚠ 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-pro41arg (accessed [today's date]).

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