Is TRPV4 p.Asp263= (c.789T>C) pathogenic?

TRPV4 p.Asp263= (c.789T>C) is classified Benign in TRPV4 (ClinVar, Multiple submitters, 11 submitters; last evaluated 2026-02-04). Common (popmax 22.3%, afr) — too common for a highly-penetrant pathogenic allele; Associated with Charcot-Marie-Tooth disease.

What condition is associated with TRPV4 p.Asp263= (c.789T>C)?

TRPV4 p.Asp263= (c.789T>C) is associated with Charcot-Marie-Tooth disease, autosomal dominant brachyolmia, metatropic dysplasia (ClinVar).

TRPV4 p.Asp263=

Q: How common is TRPV4 p.Asp263= (c.789T>C) in the general population?

TRPV4 p.Asp263= (c.789T>C) is common (popmax 22.3%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.789T>C · rs3742034 · VCV137722

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 11 submitters

gnomAD v4.1

Common

common (popmax 22.3%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

Charcot-Marie-Tooth disease

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 -4.4	GERP -4.7
Overall
CADD	0.319	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 22.3% African / African-American · 16,761/75,032 alleles

Filtering AF 22.1% ClinGen BA1/BS1 input FAF95, joint · FAF99 21.9%

Overall 9.92% 160,057/1,614,032 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	22.3%	4
South Asian	19%	5
Middle Eastern	16.4%	6
Remaining individualsnot grpmax-eligible	10%	10
Finnishnot grpmax-eligible	9.06%	11
Admixed American	8.84%	11
European (non-Finnish)	8.7%	11
East Asian	6.62%	15
Ashkenazi Jewishnot grpmax-eligible	6.4%	16
Amishnot grpmax-eligible	1.75%	57

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.Asp263=
Coding: c.789T>C
MANE Select: NM_021625
dbSNP: rs3742034
Type: single nucleotide variant
Location: chr12:109800682 (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 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

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-asp263 (accessed [today's date]).

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