NCKAP1

Chr 2

NCK associated protein 1

Also known as: HEM2, NAP1, NAP125, p125Nap1

NCBI Gene: 10787 ENSG00000061676 UniProt: Q9Y2A7 OMIM: 604891

Contributes to small GTPase binding activity. Involved in Rac protein signal transduction; positive regulation of Arp2/3 complex-mediated actin nucleation; and positive regulation of lamellipodium assembly. Located in extracellular exosome and focal adhesion. Part of SCAR complex. [provided by Alliance of Genome Resources, Jul 2025]

OMIM Research

OMIM ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.04

Clinical Summary— NCKAP1

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Gene-Disease Validity (ClinGen)

complex neurodevelopmental disorder · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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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

25 unique Pathogenic / Likely Pathogenic· 150 VUS of 233 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.04LOEUF

pLI 1.000

Z-score 7.60

OE 0.00 (0.00–0.04)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?

4.27Z-score

OE missense 0.50 (0.46–0.55)

291 obs / 580.5 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.04)

0≤0.351.4

Missense OE?0.50 (0.46–0.55)

0≤0.61.4

Synonymous OE?0.98

0≤1.21.6

LoF obs/exp: 0 / 67.2Missense obs/exp: 291 / 580.5Syn Z: 0.22

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

limitedNCKAP1-related neurodevelopmental disorderLOFAD

This gene — mechanism propensity

0.3296th %ile

GOF

0.5071th %ile

LOF

0.74top 10%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · 1 literature citation · 80% of P/LP variants are LoF · LOEUF 0.04 · ClinGen HI: Sufficient evidence for dosage pathogenicity

Literature Evidence

LOFAnazi et al. (2017) reported a heterozygous nonsense variant c.3298G>T:p.Glu1100* segregated with intellectual disability in a large multigenerational family in an effort for discovering novel genetic causes of intellectual disability. This four generation pedigree had a total of 13 affected (not a1

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

References

1.PMID 28940097 ↗

ClinVar Variant Classifications

233 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic11

Likely Pathogenic14

VUS150

Likely Benign15

Benign6

Pathogenic

Likely Pathogenic

150

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	10	0	1	0	11
Likely Pathogenic	10	4	0	0	14
VUS	4	140	5	1	150
Likely Benign	0	2	3	10	15
Benign	0	0	3	3	6
Total	24	146	12	14	196

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

View in ClinVar →

24 pathogenic / likely-pathogenic (of 30) ClinVar copy-number / structural variants overlap NCKAP1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →