Is TNNT2 p.Pro75= (c.225A>G) pathogenic?

TNNT2 p.Pro75= (c.225A>G) is classified Likely benign in TNNT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-07-08). Very rare (popmax 0.00223%, eas); Associated with hypertrophic cardiomyopathy 2.

What condition is associated with TNNT2 p.Pro75= (c.225A>G)?

TNNT2 p.Pro75= (c.225A>G) is associated with hypertrophic cardiomyopathy 2, dilated cardiomyopathy 1D, cardiomyopathy, familial restrictive, 3 (ClinVar).

How common is TNNT2 p.Pro75= (c.225A>G) in the general population?

TNNT2 p.Pro75= (c.225A>G) is very rare (popmax 0.00223%, eas) (gnomAD).

TNNT2 p.Pro75=

c.225A>G · rs2102273890 · VCV1153105

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

hypertrophic cardiomyopathy 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.4	GERP -3.6, phastCons 1
Overall
CADD	10.8	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,860 alleles

Overall 6.2e-05% 1/1,614,116 alleles · very rare exomes 1/1,461,878 · genomes 0/152,238 · joint denominator

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.Pro75=
Coding: c.225A>G
MANE Select: NM_001276345
dbSNP: rs2102273890
Type: single nucleotide variant
Location: chr1:201366846 (GRCh38)
Gene constraint: LOEUF 0.683 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 78.93 · 25 PDB
Residue 75: 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 p.Pro75Gln Uncertain significance ★ ⚠ 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
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

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-pro75 (accessed [today's date]).

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