Is TRPV4 p.Pro12= (c.36C>T) pathogenic?

TRPV4 p.Pro12= (c.36C>T) is classified Likely benign in TRPV4 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-03). Ultra-rare (popmax 0.031%, eas); Associated with Inborn genetic diseases.

What condition is associated with TRPV4 p.Pro12= (c.36C>T)?

TRPV4 p.Pro12= (c.36C>T) is associated with Inborn genetic diseases, Charcot-Marie-Tooth disease axonal type 2C (ClinVar).

How common is TRPV4 p.Pro12= (c.36C>T) in the general population?

TRPV4 p.Pro12= (c.36C>T) is ultra-rare (popmax 0.031%, eas) (gnomAD).

TRPV4 p.Pro12=

c.36C>T · rs550200361 · VCV546723

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.031%, eas)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -9.9	GERP -1.6
Overall
CADD	0.086	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.031% East Asian · 13/41,920 alleles

Filtering AF 0.0183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0145%

Overall 0.00441% 69/1,563,748 alleles · ultra-rare exomes 64/1,411,572 · genomes 5/152,176 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.031%	3,225
Remaining individualsnot grpmax-eligible	0.00989%	10,115
Admixed American	0.00757%	13,209
European (non-Finnish)	0.00389%	25,710
South Asian	0.00116%	86,002

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.Pro12=
Coding: c.36C>T
MANE Select: NM_021625
dbSNP: rs550200361
Type: single nucleotide variant
Location: chr12:109814761 (GRCh38)
Gene constraint: LOEUF 0.824 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.06 · 19 PDB
Residue 12: the 'disordered' region

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.Pro12Ser Uncertain significance ★ ⚠ same residue
TRPV4 p.Pro12Thr 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-pro12 (accessed [today's date]).

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