DIPK1A

Chr 1

divergent protein kinase domain 1A

Also known as: FAM69A

NCBI Gene: 388650 ENSG00000154511 OMIM: 614542

This gene encodes a cysteine-rich transmembrane protein that localizes to the endoplasmic reticulum, though its specific cellular function remains unknown. Mutations cause autosomal recessive spastic paraplegia with intellectual disability and seizures, typically with onset in early childhood. The gene shows moderate constraint against loss-of-function variants (LOEUF 0.494), suggesting intolerance to complete protein loss.

OMIM ResearchSummary from RefSeq

This gene encodes a member of the FAM69 family of cysteine-rich type II transmembrane proteins. These proteins localize to the endoplasmic reticulum but their specific functions are unknown. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Nov 2011]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.49

Clinical Summary— DIPK1A

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.58) — some intolerance to loss-of-function variants.

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ClinVar Variants

87 unique Pathogenic / Likely Pathogenic· 176 VUS of 398 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?

0.49LOEUF

pLI 0.584

Z-score 2.97

OE 0.19 (0.09–0.49)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

2.26Z-score

OE missense 0.56 (0.49–0.66)

120 obs / 212.6 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.19 (0.09–0.49)

0≤0.351.4

Missense OE?0.56 (0.49–0.66)

0≤0.61.4

Synonymous OE?0.89

0≤1.21.6

LoF obs/exp: 3 / 15.7Missense obs/exp: 120 / 212.6Syn Z: 0.72

This gene — mechanism propensity

0.6162th %ile

GOF

0.4579th %ile

LOF

0.3454th %ile

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and dominant-negative). The Badonyi & Marsh model scores dominant-negative highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOF93% of P/LP variants are LoF · LOEUF 0.49

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. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

398 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic56

Likely Pathogenic31

VUS176

Likely Benign93

Benign10

Conflicting10

Pathogenic

Likely Pathogenic

176

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	52	1	3	0	56
Likely Pathogenic	29	1	1	0	31
VUS	3	162	9	2	176
Likely Benign	1	2	47	43	93
Benign	0	0	8	2	10
Conflicting	—				10
Total	85	166	68	47	376

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

View in ClinVar →

7 pathogenic / likely-pathogenic (of 13) ClinVar copy-number / structural variants overlap DIPK1A — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →