TMEM167A

Chr 5

transmembrane protein 167A

Also known as: TMEM167, kish

NCBI Gene: 153339 ENSG00000174695 UniProt: Q8TBQ9 OMIM: 620000

TMEM167A encodes a protein involved in the early secretory pathway and is located in the Golgi apparatus. Mutations cause autosomal recessive intellectual disability with seizures and brain malformations. This gene is not highly constrained against loss-of-function variants, consistent with a recessive inheritance pattern affecting neurodevelopment.

OMIM ResearchSummary from RefSeq, UniProt

Involved in constitutive secretory pathway. Located in Golgi apparatus. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.79

Clinical Summary— TMEM167A

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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

1 unique Pathogenic / Likely Pathogenic· 7 VUS of 21 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.79LOEUF

pLI 0.000

Z-score 0.04

OE 0.98 (0.50–1.79)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.41Z-score

OE missense 0.82 (0.61–1.09)

32 obs / 39.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.98 (0.50–1.79)

0≤0.351.4

Missense OE?0.82 (0.61–1.09)

0≤0.61.4

Synonymous OE?0.95

0≤1.21.6

LoF obs/exp: 5 / 5.1Missense obs/exp: 32 / 39.2Syn Z: 0.14

This gene — mechanism propensity

0.80top 25%

GOF

0.81top 10%

LOF

0.3163th %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

21 submitted variants in ClinVar

ClinVar

Classification Summary

Likely Pathogenic1

VUS7

Likely Pathogenic

VUS

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Total
Pathogenic	0	0
Likely Pathogenic	1	1
VUS	7	7
Likely Benign	0	0
Benign	0	0
Total	8	8

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

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7 pathogenic / likely-pathogenic (of 14) ClinVar copy-number / structural variants overlap TMEM167A — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →