Is MAP3K14 p.Pro565= (c.1695G>A) pathogenic?

MAP3K14 p.Pro565= (c.1695G>A) is classified Likely benign in MAP3K14 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-15). Ultra-rare (popmax 0.0357%, eas); Associated with NIK deficiency.

What condition is associated with MAP3K14 p.Pro565= (c.1695G>A)?

MAP3K14 p.Pro565= (c.1695G>A) is associated with NIK deficiency (ClinVar).

How common is MAP3K14 p.Pro565= (c.1695G>A) in the general population?

MAP3K14 p.Pro565= (c.1695G>A) is ultra-rare (popmax 0.0357%, eas) (gnomAD).

How is NIK deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

MAP3K14 p.Pro565=

c.1695G>A · rs371866775 · VCV1669774

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0357%, eas)

Conditions

NIK deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -12	GERP -3.8
Overall
CADD	0.394	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0357% East Asian · 16/44,880 alleles

Filtering AF 0.0223% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0182%

Overall 0.00248% 40/1,612,934 alleles · ultra-rare exomes 34/1,460,740 · genomes 6/152,194 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0357%	2,805
Admixed American	0.00503%	19,891
European (non-Finnish)	0.0017%	58,984
Remaining individualsnot grpmax-eligible	0.0016%	62,430

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: MAP3K14
Protein: p.Pro565=
Coding: c.1695G>A
MANE Select: NM_003954
dbSNP: rs371866775
Type: single nucleotide variant
Location: chr17:45271184 (GRCh38)
Gene constraint: LOEUF 0.263 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 61.00 · 8 PDB
Residue 565: the protein kinase domain; a UniProt-annotated variant site (in imd112; likely pathogenic; loss of function in non-canonical nf-kappab signal transduction; unable to phosphorylate chuk/ikka); the 'interaction with zfp91' region; an α-helix

Full MAP3K14 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

NIK deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For NIK deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

MAP3K14 p.Pro565Arg Pathogenic same residue
MAP3K14 p.Ala103Thr Uncertain significance ★★ ⚠ same condition
MAP3K14 p.Ala142Ser Uncertain significance ★★ ⚠ same condition
MAP3K14 p.Ala575Thr Uncertain significance ★★ ⚠ same condition
MAP3K14 p.Arg131His Uncertain significance ★★ ⚠ same condition
MAP3K14 p.Arg146Gln Uncertain significance ★★ ⚠ same condition
MAP3K14 p.Arg218Gln Uncertain significance ★★ ⚠ same condition
MAP3K14 p.Arg432Trp Uncertain significance ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/map3k14-p-pro565 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown