TMOD4

Chr 1

tropomodulin 4

Also known as: SK-TMOD

NCBI Gene: 29765 ENSG00000163157 UniProt: Q9NZQ9

Predicted to enable tropomyosin binding activity. Predicted to be involved in actin filament organization; muscle contraction; and myofibril assembly. Located in striated muscle thin filament. [provided by Alliance of Genome Resources, Jul 2025]

Research

ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.09

Clinical Summary— TMOD4

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

55 VUS of 62 total submissions

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.09LOEUF

pLI 0.000

Z-score 1.25

OE 0.71 (0.47–1.09)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.71Z-score

OE missense 0.86 (0.76–0.97)

177 obs / 205.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.71 (0.47–1.09)

0≤0.351.4

Missense OE?0.86 (0.76–0.97)

0≤0.61.4

Synonymous OE?0.84

0≤1.21.6

LoF obs/exp: 15 / 21.2Missense obs/exp: 177 / 205.8Syn Z: 1.05

This gene — mechanism propensity

0.7035th %ile

GOF

0.6932th %ile

LOF

0.2777th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median

GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

62 submitted variants in ClinVar

ClinVar

Classification Summary

VUS55

VUS

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Total
Pathogenic	0	0
Likely Pathogenic	0	0
VUS	55	55
Likely Benign	0	0
Benign	0	0
Total	55	55

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

15 pathogenic / likely-pathogenic (of 18) ClinVar copy-number / structural variants overlap TMOD4 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →