Is TNNT2 p.Ser2Pro (c.4T>C) pathogenic?

TNNT2 p.Ser2Pro (c.4T>C) is classified Uncertain significance in TNNT2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-03-06). AlphaMissense: ambiguous (0.4631); Very rare (popmax 0.00133%, afr); Associated with Cardiovascular phenotype.

What condition is associated with TNNT2 p.Ser2Pro (c.4T>C)?

TNNT2 p.Ser2Pro (c.4T>C) is associated with Cardiovascular phenotype, cardiomyopathy, hypertrophic cardiomyopathy 2 (ClinVar).

How common is TNNT2 p.Ser2Pro (c.4T>C) in the general population?

TNNT2 p.Ser2Pro (c.4T>C) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about TNNT2 p.Ser2Pro (c.4T>C)?

AlphaMissense predicts ambiguous (score 0.4631) — an in-silico prediction, not a clinical call.

TNNT2 p.Ser2Pro

c.4T>C · rs765584396 · VCV924914

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.4631 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.4631	ambiguous
REVEL	0.753	pathogenic-leaning
SaProt	LLR -10.12	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2, phastCons 1
Regional constraint	o/e 0.72	unconstrained · MANE · 14 kb · p 4.5e-08 · regional, not allelic
Overall
CADD	24.4	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/75,026 alleles

Overall 6.2e-05% 1/1,614,096 alleles · very rare exomes 1/1,461,840 · genomes 0/152,256 · 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.Ser2Pro
Coding: c.4T>C
MANE Select: NM_001276345
dbSNP: rs765584396
Type: single nucleotide variant
Location: chr1:201373251 (GRCh38)
Gene constraint: LOEUF 0.683 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 78.93 · 25 PDB
Residue 2: the 'disordered' region; a modified residue (n-acetylserine); a modified residue (phosphoserine; by ck2)

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.Ser2Phe 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-ser2pro (accessed [today's date]).

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