Is TNNT1 p.Ser2= (c.6G>C) pathogenic?

TNNT1 p.Ser2= (c.6G>C) is classified Likely benign in TNNT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-01-26). Ultra-rare (popmax 0.0165%, mid); Associated with nemaline myopathy 5.

What condition is associated with TNNT1 p.Ser2= (c.6G>C)?

TNNT1 p.Ser2= (c.6G>C) is associated with nemaline myopathy 5 (ClinVar).

How common is TNNT1 p.Ser2= (c.6G>C) in the general population?

TNNT1 p.Ser2= (c.6G>C) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

How is Amish nemaline myopathy inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

TNNT1 p.Ser2=

c.6G>C · rs770552250 · VCV2903695

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Conditions

nemaline myopathy 5

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 -3.8	GERP -1.6
Overall
CADD	9.061	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,060 alleles

Overall 0.000124% 2/1,613,714 alleles · ultra-rare exomes 2/1,461,412 · genomes 0/152,302 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,060
Admixed American	0.00167%	59,982

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: TNNT1
Protein: p.Ser2=
Coding: c.6G>C
MANE Select: NM_003283
dbSNP: rs770552250
Type: single nucleotide variant
Location: chr19:55147152 (GRCh38)
Gene constraint: LOEUF 1.415 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.89
Residue 2: the 'disordered' region; a modified residue (phosphoserine; by ck2)

Full TNNT1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

nemaline myopathy 5 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Amish nemaline myopathy (Orphanet):

Inheritance: Autosomal recessive
Onset: Neonatal
Prevalence: <1 / 1 000 000 (Europe)

Similar variants

TNNT1 p.Ser2Trp Uncertain significance ★★ ⚠ same residue
TNNT1 c.309+1G>A Pathogenic/Likely pathogenic ★★ same condition
TNNT1 p.Glu180Ter Pathogenic ★★ same condition
TNNT1 p.Lys248Ter Pathogenic/Likely pathogenic ★★ same condition
TNNT1 c.129-5C>G Uncertain significance ★★ same condition
TNNT1 c.387+5G>A Uncertain significance ★★ same condition
TNNT1 p.Ala25Thr Uncertain significance ★★ ⚠ same condition
TNNT1 p.Arg107Gln 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/tnnt1-p-ser2 (accessed [today's date]).

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