Is CAV3 p.Ser141Arg (c.423C>G) pathogenic?

CAV3 p.Ser141Arg (c.423C>G) is classified Pathogenic in CAV3 (ClinVar, No assertion criteria, 2 submitters; last evaluated 2006-11-14). AlphaMissense: ambiguous (0.3979); Absent from gnomAD v4.1; Associated with long QT syndrome 9.

What condition is associated with CAV3 p.Ser141Arg (c.423C>G)?

CAV3 p.Ser141Arg (c.423C>G) is associated with long QT syndrome 9 (ClinVar).

How common is CAV3 p.Ser141Arg (c.423C>G) in the general population?

CAV3 p.Ser141Arg (c.423C>G) is absent from gnomAD v4.1 (gnomAD).

How is Romano-Ward syndrome inherited?

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

What do computational predictors say about CAV3 p.Ser141Arg (c.423C>G)?

AlphaMissense predicts ambiguous (score 0.3979) — an in-silico prediction, not a clinical call.

CAV3 p.Ser141Arg

c.423C>G · rs104893713 · VCV8291

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3979 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

long QT syndrome 9

Computational evidence

Protein change
AlphaMissense	0.3979	ambiguous
REVEL	0.933	strongly pathogenic-leaning
SaProt	LLR -10.58	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 1.9, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 12 kb · p 0.021 · regional, not allelic
Overall
CADD	24.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CAV3
Protein: p.Ser141Arg
Coding: c.423C>G
MANE Select: NM_033337
dbSNP: rs104893713
Type: single nucleotide variant
Location: chr3:8745834 (GRCh38)
Gene constraint: LOEUF 1.064 · pLI 0.04 (gnomAD)
Structure: AlphaFold pLDDT 88.54
Residue 141: a UniProt-annotated variant site (in lqt9; increase in late sodium current)

Full CAV3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

long QT syndrome 9 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Romano-Ward syndrome (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: All ages
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

CAV3 p.Ser141Asn Uncertain significance ★ ⚠ same residue
CAV3 p.Ser141= Likely benign ★ same residue
CAV3 c.114+2T>C Pathogenic ★★ same condition
CAV3 p.Arg27Gln Pathogenic ★★ same condition
CAV3 c.*134G>A Uncertain significance ★★ same condition
CAV3 c.*592G>A Uncertain significance ★★ same condition
CAV3 c.*658T>A Uncertain significance ★★ same condition
CAV3 c.*741G>A Uncertain significance ★★ 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/cav3-p-ser141arg (accessed [today's date]).

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