Is TNNT2 p.Phe80Val (c.238T>G) pathogenic?

TNNT2 p.Phe80Val (c.238T>G) is classified Uncertain significance in TNNT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-09). AlphaMissense: likely benign (0.2937); Absent from gnomAD v4.1; Associated with hypertrophic cardiomyopathy 2.

What condition is associated with TNNT2 p.Phe80Val (c.238T>G)?

TNNT2 p.Phe80Val (c.238T>G) is associated with hypertrophic cardiomyopathy 2, dilated cardiomyopathy 1D, cardiomyopathy, familial restrictive, 3 (ClinVar).

How common is TNNT2 p.Phe80Val (c.238T>G) in the general population?

TNNT2 p.Phe80Val (c.238T>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TNNT2 p.Phe80Val (c.238T>G)?

AlphaMissense predicts likely benign (score 0.2937) — an in-silico prediction, not a clinical call.

TNNT2 p.Phe80Val

c.238T>G · VCV4789271

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2937 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

hypertrophic cardiomyopathy 2

Computational evidence

Protein change
AlphaMissense	0.2937	likely benign
REVEL	0.509	indeterminate
SaProt	LLR -8.68	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9	GERP 1.8, phastCons 1
Regional constraint	o/e 0.72	unconstrained · MANE · 14 kb · p 4.5e-08 · regional, not allelic
Overall
CADD	24.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: TNNT2
Protein: p.Phe80Val
Coding: c.238T>G
MANE Select: NM_001276345
Type: single nucleotide variant
Location: chr1:201365666 (GRCh38)
Gene constraint: LOEUF 0.683 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 78.93 · 25 PDB
Residue 80: the 'disordered' region; a UniProt-annotated variant site (in cmh2)

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.Phe80Leu Uncertain significance ★★ ⚠ same residue
TNNT2 p.Phe80Ile 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

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-phe80val (accessed [today's date]).

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