Is TRPV4 p.Pro799Ser (c.2395C>T) pathogenic?

TRPV4 p.Pro799Ser (c.2395C>T) is classified Pathogenic in TRPV4 (ClinVar, No assertion criteria, 2 submitters; last evaluated 2010-10-01). AlphaMissense: likely pathogenic (0.9953); Absent from gnomAD v4.1; Associated with metatropic dysplasia.

What condition is associated with TRPV4 p.Pro799Ser (c.2395C>T)?

TRPV4 p.Pro799Ser (c.2395C>T) is associated with metatropic dysplasia, skeletal dysplasia (ClinVar).

How common is TRPV4 p.Pro799Ser (c.2395C>T) in the general population?

TRPV4 p.Pro799Ser (c.2395C>T) is absent from gnomAD v4.1 (gnomAD).

How is Metatropic dysplasia inherited?

Typically Autosomal dominant, Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about TRPV4 p.Pro799Ser (c.2395C>T)?

AlphaMissense predicts likely pathogenic (score 0.9953) — an in-silico prediction, not a clinical call.

TRPV4 p.Pro799Ser

c.2395C>T · rs267607147 · VCV18431

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9953 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

metatropic dysplasia

Computational evidence

Protein change
AlphaMissense	0.9953	likely pathogenic ✓ concordant with ClinVar · top 6% in TRPV4
REVEL	0.84	moderately pathogenic-leaning
SaProt	LLR -2.30	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does 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 0.68	unconstrained · MANE · 8,802 bp · p 1.8e-09 · regional, not allelic
Overall
CADD	24.2	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.Pro799Ser
Coding: c.2395C>T
MANE Select: NM_021625
dbSNP: rs267607147
Type: single nucleotide variant
Location: chr12:109784379 (GRCh38)
Gene constraint: LOEUF 0.824 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.06 · 19 PDB
Residue 799: a UniProt-annotated variant site (in mtd); a UniProt-annotated variant site (in mtd; also found in a patient with spondyloepiphyseal dysplasia maroteaux type)

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

Disease context

metatropic dysplasia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: skeletal dysplasia

For Metatropic dysplasia (Orphanet):

Inheritance: Autosomal dominant, Not applicable
Onset: Antenatal, Neonatal

Similar variants

TRPV4 p.Pro799Leu Pathogenic ★★ ⚠ same residue
TRPV4 p.Pro799Arg Likely pathogenic ★ ⚠ same residue
TRPV4 p.Pro799Ala Pathogenic ⚠ same residue
TRPV4 p.Pro799fs Pathogenic same residue
TRPV4 p.Pro799Gln Uncertain significance ★ ⚠ same residue
TRPV4 p.Pro799Thr Uncertain significance ★ ⚠ same residue
TRPV4 p.Pro799= Likely benign ★ same residue
TRPV4 p.Arg232Cys 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-pro799ser (accessed [today's date]).

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