Is TRPV4 p.Ala2= (c.6G>A) pathogenic?

TRPV4 p.Ala2= (c.6G>A) is classified Likely benign in TRPV4 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-27). Very rare (popmax 0.00119%, sas); Associated with Charcot-Marie-Tooth disease axonal type 2C.

What condition is associated with TRPV4 p.Ala2= (c.6G>A)?

TRPV4 p.Ala2= (c.6G>A) is associated with Charcot-Marie-Tooth disease axonal type 2C (ClinVar).

How common is TRPV4 p.Ala2= (c.6G>A) in the general population?

TRPV4 p.Ala2= (c.6G>A) is very rare (popmax 0.00119%, sas) (gnomAD).

TRPV4 p.Ala2=

Q: How is Autosomal dominant Charcot-Marie-Tooth disease type 2C inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.6G>A · rs1392798743 · VCV1123214

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00119%, sas)

Conditions

Charcot-Marie-Tooth disease axonal type 2C

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 -9.7	GERP -2.6
Overall
CADD	7.841	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00119% South Asian · 1/84,196 alleles

Filtering AF 0.000188% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000124%

Overall 0.000576% 8/1,389,350 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00167%	59,970
South Asiangrpmax	0.00119%	84,196
European (non-Finnish)	0.000523%	191,269

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala2=
Coding: c.6G>A
MANE Select: NM_021625
dbSNP: rs1392798743
Type: single nucleotide variant
Location: chr12:109814791 (GRCh38)
Gene constraint: LOEUF 0.824 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.06 · 19 PDB
Residue 2: the 'disordered' region

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

Disease context

Charcot-Marie-Tooth disease axonal type 2C — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Autosomal dominant Charcot-Marie-Tooth disease type 2C (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood, Infancy

Similar variants

TRPV4 p.Ala2Val 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-ala2 (accessed [today's date]).

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