Is TRPV4 p.Arg76= (c.228C>T) pathogenic?

TRPV4 p.Arg76= (c.228C>T) is classified Likely benign in TRPV4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-30). Very rare (popmax 0.00329%, sas); Associated with Charcot-Marie-Tooth disease axonal type 2C.

What condition is associated with TRPV4 p.Arg76= (c.228C>T)?

TRPV4 p.Arg76= (c.228C>T) is associated with Charcot-Marie-Tooth disease axonal type 2C (ClinVar).

How common is TRPV4 p.Arg76= (c.228C>T) in the general population?

TRPV4 p.Arg76= (c.228C>T) is very rare (popmax 0.00329%, sas) (gnomAD).

TRPV4 p.Arg76=

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.228C>T · rs756080811 · VCV2861245

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00329%, sas)

Conditions

Charcot-Marie-Tooth disease axonal type 2C

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1.3	GERP 1.2, phastCons 1
Overall
CADD	13.61	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00329% South Asian · 3/91,082 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.000186% 3/1,614,104 alleles · very rare exomes 3/1,461,870 · genomes 0/152,234 · 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.Arg76=
Coding: c.228C>T
MANE Select: NM_021625
dbSNP: rs756080811
Type: single nucleotide variant
Location: chr12:109814569 (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.Arg76Leu Uncertain significance ★★ same residue
TRPV4 p.Arg76Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
TRPV4 p.Arg76His Uncertain significance ★ ⚠ 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

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-arg76 (accessed [today's date]).

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