PIDD1

Chr 11AR

p53-induced death domain protein 1

Also known as: LRDD, MRT75, PIDD, altPIDD1

NCBI Gene: 55367 ENSG00000177595 UniProt: C0HMD6 OMIM: 605247

PIDD1 encodes a protein containing leucine-rich repeats and a death domain that functions as an adaptor protein in cell death signaling pathways and serves as an effector of p53-dependent apoptosis in response to DNA damage. Mutations cause autosomal recessive intellectual developmental disorder with neuropsychiatric features and variant lissencephaly, indicating early neurodevelopmental involvement. This condition follows an autosomal recessive inheritance pattern.

OMIM ResearchSummary from RefSeq, OMIM

The protein encoded by this gene contains a leucine-rich repeat and a death domain. This protein has been shown to interact with other death domain proteins, such as Fas (TNFRSF6)-associated via death domain (FADD) and MAP-kinase activating death domain-containing protein (MADD), and thus may function as an adaptor protein in cell death-related signaling processes. The expression of the mouse counterpart of this gene has been found to be positively regulated by the tumor suppressor p53 and to induce cell apoptosis in response to DNA damage, which suggests a role for this gene as an effector of p53-dependent apoptosis. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2010]

OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 1.101 OMIM phenotype

Clinical Summary— PIDD1

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Gene-Disease Validity (ClinGen)

intellectual developmental disorder, autosomal recessive 75, with neuropsychiatric features and variant lissencephaly · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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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

17 unique Pathogenic / Likely Pathogenic· 223 VUS of 337 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.10LOEUF

pLI 0.000

Z-score 1.07

OE 0.81 (0.60–1.10)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.84Z-score

OE missense 1.10 (1.03–1.17)

634 obs / 577.3 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.81 (0.60–1.10)

0≤0.351.4

Missense OE?1.10 (1.03–1.17)

0≤0.61.4

Synonymous OE?1.14

0≤1.21.6

LoF obs/exp: 29 / 35.9Missense obs/exp: 634 / 577.3Syn Z: -1.74

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongPIDD1-related neurodevelopmental disorderLOFAR

This gene — mechanism propensity

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

0.6064th %ile

GOF

0.72top 25%

LOF

0.3065th %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.

ClinVar Variant Classifications

337 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic10

Likely Pathogenic7

VUS223

Likely Benign52

Benign13

Conflicting7

Pathogenic

Likely Pathogenic

223

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	8	2	0	0	10
Likely Pathogenic	7	0	0	0	7
VUS	0	221	1	1	223
Likely Benign	0	21	7	24	52
Benign	0	4	3	6	13
Conflicting	—				7
Total	15	248	11	31	312

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

View in ClinVar →

27 pathogenic / likely-pathogenic (of 41) ClinVar copy-number / structural variants overlap PIDD1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →