NDC1

Chr 1AR

NDC1 transmembrane nucleoporin

Also known as: NEDAPA, NET3, TMEM48

NCBI Gene: 55706 ENSG00000058804 UniProt: Q9BTX1 OMIM: 610115

NDC1 encodes a component of the nuclear pore complex that is required for nuclear pore assembly and anchoring in the nuclear envelope membrane. Mutations cause a neurodevelopmental disorder with achalasia, polyneuropathy, and alacrima, inherited in an autosomal recessive pattern. This gene is highly constrained against loss-of-function variants, indicating its essential cellular role.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

A structural constituent of nuclear pore. Involved in nuclear pore complex assembly and nuclear pore localization. Located in actin cytoskeleton; nuclear membrane; and plasma membrane. Part of nuclear pore. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.241 OMIM phenotype

Clinical Summary— NDC1

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

1 unique Pathogenic / Likely Pathogenic· 93 VUS of 137 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.24LOEUF

pLI 0.999

Z-score 5.17

OE 0.10 (0.05–0.24)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

1.09Z-score

OE missense 0.83 (0.76–0.92)

290 obs / 347.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.10 (0.05–0.24)

0≤0.351.4

Missense OE?0.83 (0.76–0.92)

0≤0.61.4

Synonymous OE?1.10

0≤1.21.6

LoF obs/exp: 4 / 38.7Missense obs/exp: 290 / 347.4Syn Z: -0.87

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

moderateNDC1-related neurodevelopmental disorder with achalasia, polyneuropathy, and alacrima (triple A-like syndrome)LOFAR

This gene — mechanism propensity

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

0.3892th %ile

GOF

0.2895th %ile

LOF

0.74top 10%

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

137 submitted variants in ClinVar

ClinVar

Classification Summary

Likely Pathogenic1

VUS93

Likely Benign5

Likely Pathogenic

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Total
Pathogenic	0	0	0	0
Likely Pathogenic	0	0	1	1
VUS	1	92	0	93
Likely Benign	0	5	0	5
Benign	0	0	0	0
Total	1	97	1	99

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

View in ClinVar →

12 pathogenic / likely-pathogenic (of 18) ClinVar copy-number / structural variants overlap NDC1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →