Is MAP3K14 p.Ala645= (c.1935G>A) pathogenic?

MAP3K14 p.Ala645= (c.1935G>A) is classified Likely benign in MAP3K14 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-17). Very rare (popmax 0.00668%, amr); Associated with NIK deficiency.

What condition is associated with MAP3K14 p.Ala645= (c.1935G>A)?

MAP3K14 p.Ala645= (c.1935G>A) is associated with NIK deficiency (ClinVar).

How common is MAP3K14 p.Ala645= (c.1935G>A) in the general population?

MAP3K14 p.Ala645= (c.1935G>A) is very rare (popmax 0.00668%, amr) (gnomAD).

How is NIK deficiency inherited?

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

MAP3K14 p.Ala645=

c.1935G>A · rs535912575 · VCV2414030

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00668%, amr)

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 -4.7	GERP -3.8
Overall
CADD	3.256	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00668% Admixed American · 4/59,922 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.00186% 30/1,612,260 alleles · very rare exomes 29/1,460,016 · genomes 1/152,244 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00668%	14,981
Remaining individualsnot grpmax-eligible	0.00642%	15,581
East Asian	0.00223%	44,812
European (non-Finnish)	0.0017%	58,980
South Asian	0.0011%	91,018

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.Ala645=
Coding: c.1935G>A
MANE Select: NM_003954
dbSNP: rs535912575
Type: single nucleotide variant
Location: chr17:45270450 (GRCh38)
Gene constraint: LOEUF 0.263 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 61.00 · 8 PDB
Residue 645: the protein kinase domain; 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.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
MAP3K14 p.Arg99His 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-ala645 (accessed [today's date]).

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