TMEM203

Chr 9

transmembrane protein 203

Also known as: HBEBP1

NCBI Gene: 94107 ENSG00000187713 UniProt: Q969S6 OMIM: 616499

TMEM203 encodes a transmembrane protein that regulates intracellular calcium homeostasis and modulates STING-mediated innate immune signaling pathways. Mutations cause autosomal recessive developmental and epileptic encephalopathy with onset in infancy, characterized by severe intellectual disability, refractory seizures, and progressive microcephaly. The gene shows moderate constraint against loss-of-function variants, suggesting haploinsufficiency may be tolerated while biallelic loss causes severe neurodevelopmental phenotypes.

OMIM ResearchSummary from RefSeq, UniProt

Involved in intracellular calcium ion homeostasis. Located in endoplasmic reticulum. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.92

Clinical Summary— TMEM203

⚡

Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.63) — some intolerance to loss-of-function variants.

📋

ClinVar Variants

1 unique Pathogenic / Likely Pathogenic· 15 VUS of 16 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.92LOEUF

pLI 0.634

Z-score 1.66

OE 0.00 (0.00–0.92)

Moderately constrained

Typical tolerance to LoF variation

Missense Constraint?

1.81Z-score

OE missense 0.42 (0.32–0.56)

32 obs / 76.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.92)

0≤0.351.4

Missense OE?0.42 (0.32–0.56)

0≤0.61.4

Synonymous OE?0.92

0≤1.21.6

LoF obs/exp: 0 / 3.2Missense obs/exp: 32 / 76.4Syn Z: 0.37

This gene — mechanism propensity

0.6648th %ile

GOF

0.89top 5%

LOF

0.3164th %ile

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

GOFprediction above median

DNprediction 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

16 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1

VUS15

Pathogenic

VUS

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Total
Pathogenic	1	0	1
Likely Pathogenic	0	0	0
VUS	0	15	15
Likely Benign	0	0	0
Benign	0	0	0
Total	1	15	16

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

View in ClinVar →

93 pathogenic / likely-pathogenic (of 106) ClinVar copy-number / structural variants overlap TMEM203 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →