Is TRPV4 p.Pro749= (c.2247C>T) pathogenic?

TRPV4 p.Pro749= (c.2247C>T) is classified Conflicting classifications of pathogenicity in TRPV4 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-04-14). Ultra-rare (popmax 0.0165%, mid); Associated with Inborn genetic diseases.

What condition is associated with TRPV4 p.Pro749= (c.2247C>T)?

TRPV4 p.Pro749= (c.2247C>T) is associated with Inborn genetic diseases, Charcot-Marie-Tooth disease axonal type 2C (ClinVar).

How common is TRPV4 p.Pro749= (c.2247C>T) in the general population?

TRPV4 p.Pro749= (c.2247C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

TRPV4 p.Pro749=

c.2247C>T · rs141135321 · VCV593378

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

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 -9.4	GERP -4.7
Overall
CADD	4.133	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,062 alleles

Filtering AF 0.00443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00403%

Overall 0.00533% 86/1,614,044 alleles · ultra-rare exomes 77/1,461,746 · genomes 9/152,298 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
Admixed American	0.01%	10,004
African / African-American	0.00666%	15,008
South Asian	0.00659%	15,180
European (non-Finnish)	0.00551%	18,154
Remaining individualsnot grpmax-eligible	0.0048%	20,836

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.Pro749=
Coding: c.2247C>T
MANE Select: NM_021625
dbSNP: rs141135321
Type: single nucleotide variant
Location: chr12:109786799 (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

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

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

Similar variants

TRPV4 p.Pro749Arg 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
TRPV4 p.Arg316Cys 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-pro749 (accessed [today's date]).

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