Is CFTR p.Ala196Val (c.587C>T) pathogenic?

CFTR p.Ala196Val (c.587C>T) is classified Uncertain significance in CFTR (ClinVar, Single submitter, 2 submitters; last evaluated 2021-08-27). AlphaMissense: ambiguous (0.4177); Very rare (popmax 0.00102%, nfe); Associated with cystic fibrosis.

What condition is associated with CFTR p.Ala196Val (c.587C>T)?

CFTR p.Ala196Val (c.587C>T) is associated with cystic fibrosis (ClinVar).

How common is CFTR p.Ala196Val (c.587C>T) in the general population?

CFTR p.Ala196Val (c.587C>T) is very rare (popmax 0.00102%, 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.Ala196Val (c.587C>T)?

AlphaMissense predicts ambiguous (score 0.4177) — an in-silico prediction, not a clinical call.

CFTR p.Ala196Val

c.587C>T · rs1204822296 · VCV861611

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4177 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00102%, nfe)

Conditions

cystic fibrosis

Computational evidence

Protein change
AlphaMissense	0.4177	ambiguous
REVEL	0.629	indeterminate
SaProt	LLR -6.63	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.6, phastCons 1
Regional constraint	o/e 1.13	unconstrained · MANE · 187 kb · p 2.1e-08 · regional, not allelic
Overall
CADD	26.1	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 0.00102% European (non-Finnish) · 12/1,179,996 alleles

Filtering AF 0.000542% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000428%

Overall 0.000889% 13/1,461,848 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,508
European (non-Finnish)grpmax	0.00102%	98,333

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.Ala196Val
Coding: c.587C>T
MANE Select: NM_000492
dbSNP: rs1204822296
Type: single nucleotide variant
Location: chr7:117535255 (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 196: the abc transmembrane type-1 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.Ala196Pro Uncertain significance ★★ ⚠ same residue
CFTR p.Ala196= Likely benign ★★ same residue
CFTR p.Ala196Gly Uncertain significance ★ ⚠ same residue
CFTR p.Ala196Thr Uncertain significance ★ ⚠ same residue
CFTR p.Ala196fs 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-ala196val (accessed [today's date]).

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