PTRH2

Chr 17AR

peptidyl-tRNA hydrolase 2

Also known as: BIT1, CFAP37, CGI-147, IMNEPD, PTH 2, PTH2

NCBI Gene: 51651 ENSG00000141378 UniProt: Q9Y3E5 OMIM: 608625

The encoded mitochondrial protein functions as a peptidyl-tRNA hydrolase that releases tRNAs from ribosomes during protein synthesis and regulates cell survival and apoptosis pathways. Mutations cause infantile-onset multisystem neurologic, endocrine, and pancreatic disease characterized by intellectual disability, postnatal microcephaly, progressive cerebellar atrophy, hearing impairment, polyneuropathy, failure to thrive, and organ fibrosis with exocrine pancreatic insufficiency. This condition follows autosomal recessive inheritance with onset in infancy affecting neurologic, endocrine, and gastrointestinal systems.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene is a mitochondrial protein with two putative domains, an N-terminal mitochondrial localization sequence, and a UPF0099 domain. In vitro assays suggest that this protein possesses peptidyl-tRNA hydrolase activity, to release the peptidyl moiety from tRNA, thereby preventing the accumulation of dissociated peptidyl-tRNA that could reduce the efficiency of translation. This protein also plays a role regulating cell survival and death. It promotes survival as part of an integrin-signaling pathway for cells attached to the extracellular matrix (ECM), but also promotes apoptosis in cells that have lost their attachment to the ECM, a process called anoikos. After loss of cell attachment to the ECM, this protein is phosphorylated, is released from the mitochondria into the cytosol, and promotes caspase-independent apoptosis through interactions with transcriptional regulators. This gene has been implicated in the development and progression of tumors, and mutations in this gene have been associated with an infantile multisystem neurologic, endocrine, and pancreatic disease (INMEPD) characterized by intellectual disability, postnatal microcephaly, progressive cerebellar atrophy, hearing impairment, polyneuropathy, failure to thrive, and organ fibrosis with exocrine pancreas insufficiency (PMID: 25574476). Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Mar 2015]

OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 1.701 OMIM phenotype

Clinical Summary— PTRH2

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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

9 unique Pathogenic / Likely Pathogenic· 24 VUS of 52 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?

1.70LOEUF

pLI 0.001

Z-score 0.28

OE 0.87 (0.45–1.70)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.43Z-score

OE missense 0.88 (0.73–1.05)

83 obs / 94.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.87 (0.45–1.70)

0≤0.351.4

Missense OE?0.88 (0.73–1.05)

0≤0.61.4

Synonymous OE?1.15

0≤1.21.6

LoF obs/exp: 5 / 5.7Missense obs/exp: 83 / 94.7Syn Z: -0.68

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitivePTRH2-related neurologic, endocrine, and pancreatic disease, multisystem, infantile-onsetLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.6452th %ile

GOF

0.2597th %ile

LOF

0.4037th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

52 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic2

Likely Pathogenic7

VUS24

Likely Benign16

Benign1

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	1	1	0	0	2
Likely Pathogenic	6	1	0	0	7
VUS	2	21	1	0	24
Likely Benign	0	2	8	6	16
Benign	0	0	1	0	1
Total	9	25	10	6	50

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

View in ClinVar →

15 pathogenic / likely-pathogenic (of 17) ClinVar copy-number / structural variants overlap PTRH2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →