Is TRPV4 p.Ser46Phe (c.137C>T) pathogenic?

TRPV4 p.Ser46Phe (c.137C>T) is classified Conflicting classifications of pathogenicity in TRPV4 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-12-17). AlphaMissense: likely benign (0.1318); Ultra-rare (popmax 0.0213%, nfe); Associated with Inborn genetic diseases.

What condition is associated with TRPV4 p.Ser46Phe (c.137C>T)?

TRPV4 p.Ser46Phe (c.137C>T) is associated with Inborn genetic diseases, Charcot-Marie-Tooth disease axonal type 2C, Charcot-Marie-Tooth disease (ClinVar).

How common is TRPV4 p.Ser46Phe (c.137C>T) in the general population?

TRPV4 p.Ser46Phe (c.137C>T) is ultra-rare (popmax 0.0213%, nfe) (gnomAD).

What do computational predictors say about TRPV4 p.Ser46Phe (c.137C>T)?

AlphaMissense predicts likely benign (score 0.1318) — an in-silico prediction, not a clinical call.

TRPV4 p.Ser46Phe

c.137C>T · rs202066574 · VCV469035

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1318 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0213%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1318	likely benign
REVEL	0.387	indeterminate
SaProt	LLR -8.62	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.3	GERP 1.2, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 208 bp · p 0.45 · regional, not allelic
Overall
CADD	22.4	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0213% European (non-Finnish) · 251/1,179,836 alleles

Filtering AF 0.0191% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0183%

Overall 0.0158% 255/1,613,392 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0213%	4,701
Remaining individualsnot grpmax-eligible	0.0032%	31,239
Admixed American	0.00167%	59,972
African / African-American	0.00133%	75,048

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.Ser46Phe
Coding: c.137C>T
MANE Select: NM_021625
dbSNP: rs202066574
Type: single nucleotide variant
Location: chr12:109814660 (GRCh38)
Gene constraint: LOEUF 0.824 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.06 · 19 PDB
Residue 46: 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 Charcot-Marie-Tooth disease

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-ser46phe (accessed [today's date]).

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