Is TNNT2 p.Pro90= (c.270C>G) pathogenic?

TNNT2 p.Pro90= (c.270C>G) is classified Conflicting classifications of pathogenicity in TNNT2 (ClinVar, Conflicting submitters, 12 submitters; last evaluated 2026-04-01). Ultra-rare (popmax 0.035%, amr); Associated with Cardiovascular phenotype.

What condition is associated with TNNT2 p.Pro90= (c.270C>G)?

TNNT2 p.Pro90= (c.270C>G) is associated with Cardiovascular phenotype, cardiomyopathy, hypertrophic cardiomyopathy 2 (ClinVar).

How common is TNNT2 p.Pro90= (c.270C>G) in the general population?

TNNT2 p.Pro90= (c.270C>G) is ultra-rare (popmax 0.035%, amr) (gnomAD).

TNNT2 p.Pro90=

c.270C>G · rs140245123 · VCV43621

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 12 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.035%, amr)

Conditions

Cardiovascular phenotype

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 -9.1	GERP -4.2
Overall
CADD	0.362	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.035% Admixed American · 21/60,004 alleles

Filtering AF 0.0234% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0197%

Overall 0.0188% 304/1,614,022 alleles · ultra-rare exomes 282/1,461,744 · genomes 22/152,278 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.035%	2,857
Remaining individualsnot grpmax-eligible	0.0256%	3,907
European (non-Finnish)	0.0222%	4,504
Middle Eastern	0.0165%	6,062
African / African-American	0.004%	25,013
Finnishnot grpmax-eligible	0.00156%	64,028

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.Pro90=
Coding: c.270C>G
MANE Select: NM_001276345
dbSNP: rs140245123
Type: single nucleotide variant
Location: chr1:201365634 (GRCh38)
Gene constraint: LOEUF 0.683 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 78.93 · 25 PDB
Residue 90: the 'disordered' region

Full TNNT2 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 hypertrophic cardiomyopathy 2 dilated cardiomyopathy 1D cardiomyopathy, familial restrictive, 3

Similar variants

TNNT2 p.Pro90His Uncertain significance ★ ⚠ same residue
TNNT2 p.Pro90Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
TNNT2 p.Pro90Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
TNNT2 p.Pro90Leu Pathogenic ★ same residue
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

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-pro90 (accessed [today's date]).

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