Is TNNT2 p.Arg28= (c.84A>G) pathogenic?

TNNT2 p.Arg28= (c.84A>G) is classified Likely benign in TNNT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2017-04-01). Very rare (popmax 0.0083%, nfe); Associated with hypertrophic cardiomyopathy 2.

What condition is associated with TNNT2 p.Arg28= (c.84A>G)?

TNNT2 p.Arg28= (c.84A>G) is associated with hypertrophic cardiomyopathy 2, dilated cardiomyopathy 1D, cardiomyopathy, familial restrictive, 3 (ClinVar).

How common is TNNT2 p.Arg28= (c.84A>G) in the general population?

TNNT2 p.Arg28= (c.84A>G) is very rare (popmax 0.0083%, nfe) (gnomAD).

TNNT2 p.Arg28=

c.84A>G · rs370895664 · VCV469527

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.0083%, nfe)

Conditions

hypertrophic cardiomyopathy 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.24	acceptor loss, 16 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 0.041	GERP -3.4, phastCons 0.011
Overall
CADD	10.05	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0083% European (non-Finnish) · 98/1,180,012 alleles

Filtering AF 0.00697% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00641%

Overall 0.00613% 99/1,614,002 alleles · very rare exomes 95/1,461,874 · genomes 4/152,128 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0083%	12,041
Remaining individualsnot grpmax-eligible	0.0016%	62,490

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: TNNT2
Protein: p.Arg28=
Coding: c.84A>G
MANE Select: NM_001276345
dbSNP: rs370895664
Type: single nucleotide variant
Location: chr1:201369829 (GRCh38)
Gene constraint: LOEUF 0.683 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 78.93 · 25 PDB
Residue 28: the 'disordered' region

Full TNNT2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hypertrophic cardiomyopathy 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: dilated cardiomyopathy 1D cardiomyopathy, familial restrictive, 3

Similar variants

TNNT2 c.851+1G>A Likely pathogenic ★★★ same condition
TNNT2 p.Arg104His Likely pathogenic ★★★ same condition
TNNT2 p.Trp297Ter Likely pathogenic ★★★ same condition
TNNT2 p.Arg296Cys Uncertain significance ★★★ ⚠ same condition
TNNT2 p.Arg288Cys Likely benign ★★★ same condition
TNNT2 c.851+1G>C Pathogenic/Likely pathogenic ★★ same condition
TNNT2 c.851+1G>T Pathogenic/Likely pathogenic ★★ same condition
TNNT2 p.Arg102Gln 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/tnnt2-p-arg28 (accessed [today's date]).

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