Is TMEM43 p.Pro74= (c.222C>T) pathogenic?

TMEM43 p.Pro74= (c.222C>T) is classified Benign/Likely benign in TMEM43 (ClinVar, Multiple submitters, 20 submitters; last evaluated 2026-06-01). Low-frequency (popmax 1.37%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with TMEM43 p.Pro74= (c.222C>T)?

TMEM43 p.Pro74= (c.222C>T) is associated with Cardiovascular phenotype, cardiomyopathy, arrhythmogenic right ventricular dysplasia 5 (ClinVar).

How common is TMEM43 p.Pro74= (c.222C>T) in the general population?

TMEM43 p.Pro74= (c.222C>T) is low-frequency (popmax 1.37%, nfe) (gnomAD).

TMEM43 p.Pro74=

c.222C>T · rs34099410 · VCV46141

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 20 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.37%, nfe)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.46 · evaluated, not missing
Constraint at this position
Conservation	phyloP -20	GERP -3
Overall
CADD	0.079	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.37% European (non-Finnish) · 16,212/1,179,784 alleles

Filtering AF 1.36% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.35%

Overall 1.11% 17,988/1,613,732 alleles · low-frequency exomes 16,753/1,461,458 · genomes 1,235/152,274 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	1.37%	73
Remaining individualsnot grpmax-eligible	0.926%	108
Middle Eastern	0.726%	138
Ashkenazi Jewishnot grpmax-eligible	0.635%	157
Admixed American	0.607%	165
Finnishnot grpmax-eligible	0.358%	279
African / African-American	0.245%	408
South Asian	0.207%	484

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.Pro74=
Coding: c.222C>T
MANE Select: NM_024334
dbSNP: rs34099410
Type: single nucleotide variant
Location: chr3:14130881 (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

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: cardiomyopathy arrhythmogenic right ventricular dysplasia 5 Emery-Dreifuss muscular dystrophy 7, autosomal dominant auditory neuropathy, autosomal dominant 3

Similar variants

TMEM43 p.Pro74Ser Uncertain significance ★★ ⚠ 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
TMEM43 c.162+1G>A Uncertain significance ★★ same condition
TMEM43 c.163-1G>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-pro74 (accessed [today's date]).

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