Is TRPV4 p.Pro82Arg (c.245C>G) pathogenic?

TRPV4 p.Pro82Arg (c.245C>G) is classified Uncertain significance in TRPV4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-21). AlphaMissense: likely benign (0.1146); Absent from gnomAD v4.1; Associated with Charcot-Marie-Tooth disease axonal type 2C.

What condition is associated with TRPV4 p.Pro82Arg (c.245C>G)?

TRPV4 p.Pro82Arg (c.245C>G) is associated with Charcot-Marie-Tooth disease axonal type 2C (ClinVar).

How common is TRPV4 p.Pro82Arg (c.245C>G) in the general population?

TRPV4 p.Pro82Arg (c.245C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TRPV4 p.Pro82Arg (c.245C>G)?

AlphaMissense predicts likely benign (score 0.1146) — an in-silico prediction, not a clinical call.

TRPV4 p.Pro82Arg

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.245C>G · rs767079858 · VCV1041173

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1146 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Charcot-Marie-Tooth disease axonal type 2C

Computational evidence

Protein change
AlphaMissense	0.1146	likely benign
REVEL	0.786	moderately pathogenic-leaning
SaProt	LLR -6.31	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 12	GERP 1.2, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 22 kb · p 2.6e-10 · regional, not allelic
Overall
CADD	26.7	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: TRPV4
Protein: p.Pro82Arg
Coding: c.245C>G
MANE Select: NM_021625
dbSNP: rs767079858
Type: single nucleotide variant
Location: chr12:109814552 (GRCh38)
Gene constraint: LOEUF 0.824 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.06 · 19 PDB

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.Pro82Ser Uncertain significance ★ ⚠ same residue
TRPV4 p.Pro82Leu Pathogenic ★ ⚠ same residue
TRPV4 p.Arg186Gln Pathogenic/Likely pathogenic ★★ same condition
TRPV4 p.Arg232Cys 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-pro82arg (accessed [today's date]).

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