Is CFTR p.Phe992Val (c.2974T>G) pathogenic?

CFTR p.Phe992Val (c.2974T>G) is classified Uncertain significance in CFTR (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-01). AlphaMissense: likely pathogenic (0.7316); Very rare (popmax 0.0027%, afr); Associated with cystic fibrosis.

What condition is associated with CFTR p.Phe992Val (c.2974T>G)?

CFTR p.Phe992Val (c.2974T>G) is associated with cystic fibrosis (ClinVar).

How common is CFTR p.Phe992Val (c.2974T>G) in the general population?

CFTR p.Phe992Val (c.2974T>G) is very rare (popmax 0.0027%, afr) (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.Phe992Val (c.2974T>G)?

AlphaMissense predicts likely pathogenic (score 0.7316) — an in-silico prediction, not a clinical call.

CFTR p.Phe992Val

c.2974T>G · VCV4227383

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7316 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0027%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cystic fibrosis

Computational evidence

Protein change
AlphaMissense	0.7316	likely pathogenic
REVEL	0.789	moderately pathogenic-leaning
SaProt	LLR -7.64	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP -0.69, phastCons 1
Regional constraint	o/e 1.13	unconstrained · MANE · 187 kb · p 2.1e-08 · regional, not allelic
Overall
CADD	26.6	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 0.0027% African / African-American · 2/73,990 alleles

Filtering AF 0.000449% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000168%

Overall 0.00131% 2/152,170 alleles · very rare

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.Phe992Val
Coding: c.2974T>G
MANE Select: NM_000492
Type: single nucleotide variant
Location: chr7:117606739 (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 992: a UniProt-annotated variant site (in cf); the abc transmembrane type-1 2 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

For Cystic fibrosis (Orphanet):

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

Similar variants

CFTR p.Phe992Leu 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
CFTR c.579+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-phe992val (accessed [today's date]).

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