Is TRPV4 p.Pro19= (c.57C>T) pathogenic?

TRPV4 p.Pro19= (c.57C>T) is classified Benign/Likely benign in TRPV4 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-01-13). Rare (popmax 0.531%, afr); Associated with Inborn genetic diseases.

What condition is associated with TRPV4 p.Pro19= (c.57C>T)?

TRPV4 p.Pro19= (c.57C>T) is associated with Inborn genetic diseases, Charcot-Marie-Tooth disease axonal type 2C, Charcot-Marie-Tooth disease (ClinVar).

How common is TRPV4 p.Pro19= (c.57C>T) in the general population?

TRPV4 p.Pro19= (c.57C>T) is rare (popmax 0.531%, afr) (gnomAD).

TRPV4 p.Pro19=

c.57C>T · rs112408790 · VCV440358

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

gnomAD v4.1

Rare

rare (popmax 0.531%, afr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -6.3	GERP -2.6
Overall
CADD	0.321	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.531% African / African-American · 395/74,430 alleles

Filtering AF 0.487% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.47%

Overall 0.0321% 509/1,587,004 alleles · rare exomes 276/1,434,800 · genomes 233/152,204 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.531%	188
Middle Eastern	0.101%	990
Remaining individualsnot grpmax-eligible	0.0488%	2,049
Admixed American	0.0375%	2,668
European (non-Finnish)	0.00471%	21,239
South Asian	0.00227%	44,007

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.Pro19=
Coding: c.57C>T
MANE Select: NM_021625
dbSNP: rs112408790
Type: single nucleotide variant
Location: chr12:109814740 (GRCh38)
Gene constraint: LOEUF 0.824 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.06 · 19 PDB
Residue 19: the 'disordered' region; a UniProt-annotated variant site (associated with lower sodium concentrations in serum; shows diminished response to hypotonic stress relative to wild-type)

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Charcot-Marie-Tooth disease axonal type 2C Charcot-Marie-Tooth disease

Similar variants

TRPV4 p.Pro19Ser Benign ★★ same residue
TRPV4 p.Pro19His 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
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-pro19 (accessed [today's date]).

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