Is TRPV4 p.Pro57= (c.171T>C) pathogenic?

TRPV4 p.Pro57= (c.171T>C) is classified Conflicting classifications of pathogenicity in TRPV4 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2019-07-11). Very rare (popmax 0.00223%, eas); Associated with scapuloperoneal spinal muscular atrophy, autosomal dominant.

What condition is associated with TRPV4 p.Pro57= (c.171T>C)?

TRPV4 p.Pro57= (c.171T>C) is associated with scapuloperoneal spinal muscular atrophy, autosomal dominant, autosomal dominant brachyolmia, metatropic dysplasia (ClinVar).

How common is TRPV4 p.Pro57= (c.171T>C) in the general population?

TRPV4 p.Pro57= (c.171T>C) is very rare (popmax 0.00223%, eas) (gnomAD).

How is Scapuloperoneal spinal muscular atrophy inherited?

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

TRPV4 p.Pro57=

c.171T>C · rs886048941 · VCV307144

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

scapuloperoneal spinal muscular atrophy, autosomal dominant

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 -2.1	GERP -2.4
Overall
CADD	1.156	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,856 alleles

Overall 6.2e-05% 1/1,613,966 alleles · very rare exomes 1/1,461,672 · genomes 0/152,294 · 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.Pro57=
Coding: c.171T>C
MANE Select: NM_021625
dbSNP: rs886048941
Type: single nucleotide variant
Location: chr12:109814626 (GRCh38)
Gene constraint: LOEUF 0.824 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.06 · 19 PDB
Residue 57: the 'disordered' region

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

Disease context

scapuloperoneal spinal muscular atrophy, autosomal dominant — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: autosomal dominant brachyolmia metatropic dysplasia spondylometaphyseal dysplasia, Kozlowski type neuronopathy, distal hereditary motor, autosomal dominant 8 Charcot-Marie-Tooth disease axonal type 2C

For Scapuloperoneal spinal muscular atrophy (Orphanet):

Inheritance: Autosomal dominant
Onset: Childhood, Infancy, Neonatal

Similar variants

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
TRPV4 p.Arg316Cys Pathogenic ★★ ⚠ same condition
TRPV4 p.Arg316His 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-pro57 (accessed [today's date]).

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