Is TRPV4 p.Arg232Pro (c.695G>C) pathogenic?

TRPV4 p.Arg232Pro (c.695G>C) is classified Likely pathogenic in TRPV4 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-05-13). AlphaMissense: likely pathogenic (0.9854); Very rare (popmax 8.47e-05%, nfe); Associated with Charcot-Marie-Tooth disease axonal type 2C.

What condition is associated with TRPV4 p.Arg232Pro (c.695G>C)?

TRPV4 p.Arg232Pro (c.695G>C) is associated with Charcot-Marie-Tooth disease axonal type 2C (ClinVar).

How common is TRPV4 p.Arg232Pro (c.695G>C) in the general population?

TRPV4 p.Arg232Pro (c.695G>C) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about TRPV4 p.Arg232Pro (c.695G>C)?

AlphaMissense predicts likely pathogenic (score 0.9854) — an in-silico prediction, not a clinical call.

TRPV4 p.Arg232Pro

Q: How is Autosomal dominant Charcot-Marie-Tooth disease type 2C inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.695G>C · rs769107613 · VCV1493962

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9854 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Charcot-Marie-Tooth disease axonal type 2C

Computational evidence

Protein change
AlphaMissense	0.9854	likely pathogenic ✓ concordant with ClinVar
REVEL	0.626	indeterminate
SaProt	LLR -8.32	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.7	GERP -4.1, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 22 kb · p 2.6e-10 · regional, not allelic
Overall
CADD	26.3	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 8.47e-05% European (non-Finnish) · 1/1,180,014 alleles

Overall 6.2e-05% 1/1,614,016 alleles · very rare exomes 1/1,461,708 · genomes 0/152,308 · joint denominator

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: TRPV4
Protein: p.Arg232Pro
Coding: c.695G>C
MANE Select: NM_021625
dbSNP: rs769107613
Type: single nucleotide variant
Location: chr12:109803008 (GRCh38)
Gene constraint: LOEUF 0.824 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.06 · 19 PDB
Residue 232: a UniProt-annotated variant site (in hmnd8 and cmt2c; does not affect channel localization to plasma membrane; results in increased agonist-induced channel activity and increased basal intracellular calcium concentration; decreases atp-binding; no effect on protein stability; decreases binding to membranes enriched in phosphatidylinositol-2,4-bisphosphate; causes increased cell death)

Full TRPV4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Charcot-Marie-Tooth disease axonal type 2C — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Autosomal dominant Charcot-Marie-Tooth disease type 2C (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood, Infancy

Similar variants

TRPV4 p.Arg232Cys Pathogenic ★★ ⚠ same residue
TRPV4 p.Arg232His Conflicting classifications of pathogenicity ★ same residue
TRPV4 p.Arg232Ser Uncertain significance ⚠ same residue
TRPV4 p.Arg186Gln Pathogenic/Likely pathogenic ★★ same condition
TRPV4 p.Arg269Cys Pathogenic ★★ ⚠ same condition
TRPV4 p.Arg269His Pathogenic/Likely pathogenic ★★ same condition
TRPV4 p.Arg315Gln Pathogenic/Likely pathogenic ★★ ⚠ same condition
TRPV4 p.Arg315Trp Pathogenic/Likely 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/trpv4-p-arg232pro (accessed [today's date]).

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