Is TRPV4 p.Val522= (c.1566C>G) pathogenic?

TRPV4 p.Val522= (c.1566C>G) is classified Likely benign in TRPV4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-02-24). Ultra-rare (popmax 0.0165%, mid); Associated with Inborn genetic diseases.

What condition is associated with TRPV4 p.Val522= (c.1566C>G)?

TRPV4 p.Val522= (c.1566C>G) is associated with Inborn genetic diseases, Charcot-Marie-Tooth disease axonal type 2C (ClinVar).

How common is TRPV4 p.Val522= (c.1566C>G) in the general population?

TRPV4 p.Val522= (c.1566C>G) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

TRPV4 p.Val522=

c.1566C>G · rs765724064 · VCV536874

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 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 0.64	GERP -3.6, phastCons 1
Overall
CADD	4.465	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,050 alleles

Filtering AF 0.00443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00317%

Overall 0.000807% 13/1,610,054 alleles · ultra-rare exomes 13/1,458,030 · genomes 0/152,024 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,050
South Asian	0.00893%	11,192
Remaining individualsnot grpmax-eligible	0.00321%	31,181
European (non-Finnish)	0.00017%	589,480

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.Val522=
Coding: c.1566C>G
MANE Select: NM_021625
dbSNP: rs765724064
Type: single nucleotide variant
Location: chr12:109793948 (GRCh38)
Gene constraint: LOEUF 0.824 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.06 · 19 PDB
Residue 522: an α-helix

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.Val522Ala 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-val522 (accessed [today's date]).

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