Is TMEM43 p.Pro82= (c.246G>A) pathogenic?

TMEM43 p.Pro82= (c.246G>A) is classified Benign/Likely benign in TMEM43 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2025-12-24). Ultra-rare (popmax 0.0183%, amr); Associated with arrhythmogenic right ventricular dysplasia 5.

What condition is associated with TMEM43 p.Pro82= (c.246G>A)?

TMEM43 p.Pro82= (c.246G>A) is associated with arrhythmogenic right ventricular dysplasia 5, cardiomyopathy (ClinVar).

How common is TMEM43 p.Pro82= (c.246G>A) in the general population?

TMEM43 p.Pro82= (c.246G>A) is ultra-rare (popmax 0.0183%, amr) (gnomAD).

TMEM43 p.Pro82=

Q: How is Inherited isolated arrhythmogenic cardiomyopathy inherited?

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

c.246G>A · rs376098518 · VCV343502

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0183%, amr)

Conditions

arrhythmogenic right ventricular dysplasia 5

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 -20	GERP -3
Overall
CADD	0.106	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0183% Admixed American · 11/59,968 alleles

Filtering AF 0.0102% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00786%

Overall 0.00291% 47/1,613,404 alleles · ultra-rare exomes 44/1,461,260 · genomes 3/152,144 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0183%	5,452
East Asian	0.00446%	22,441
South Asian	0.0033%	30,345
African / African-American	0.00267%	37,448
European (non-Finnish)	0.00237%	42,130
Remaining individualsnot grpmax-eligible	0.0016%	62,462

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: TMEM43
Protein: p.Pro82=
Coding: c.246G>A
MANE Select: NM_024334
dbSNP: rs376098518
Type: single nucleotide variant
Location: chr3:14130905 (GRCh38)
Gene constraint: LOEUF 1.13 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 89.92

Full TMEM43 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

arrhythmogenic right ventricular dysplasia 5 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: cardiomyopathy

For Inherited isolated arrhythmogenic cardiomyopathy (Orphanet):

Inheritance: Autosomal dominant
Onset: No data available

Similar variants

TMEM43 p.Pro82Ala Uncertain significance ★★ ⚠ same residue
TMEM43 p.Pro82Ser Uncertain significance ★★ ⚠ same residue
TMEM43 p.Pro82Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
TMEM43 p.Ser358Leu Pathogenic ★★ ⚠ same condition
TMEM43 c.1000+2T>C Uncertain significance ★★ same condition
TMEM43 c.1000+5G>T Uncertain significance ★★ same condition
TMEM43 c.1000+6T>C Uncertain significance ★★ same condition
TMEM43 c.13-1G>C 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/tmem43-p-pro82 (accessed [today's date]).

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