Is MAP3K14 p.Cys593Arg (c.1777T>C) pathogenic?

MAP3K14 p.Cys593Arg (c.1777T>C) is classified Uncertain significance in MAP3K14 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-28). AlphaMissense: likely benign (0.187); Very rare (popmax 0.000763%, nfe); Associated with NIK deficiency.

What condition is associated with MAP3K14 p.Cys593Arg (c.1777T>C)?

MAP3K14 p.Cys593Arg (c.1777T>C) is associated with NIK deficiency (ClinVar).

How common is MAP3K14 p.Cys593Arg (c.1777T>C) in the general population?

MAP3K14 p.Cys593Arg (c.1777T>C) is very rare (popmax 0.000763%, nfe) (gnomAD).

How is NIK deficiency inherited?

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

What do computational predictors say about MAP3K14 p.Cys593Arg (c.1777T>C)?

AlphaMissense predicts likely benign (score 0.187) — an in-silico prediction, not a clinical call.

MAP3K14 p.Cys593Arg

c.1777T>C · rs1480888701 · VCV1990075

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.187 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000763%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

NIK deficiency

Computational evidence

Protein change
AlphaMissense	0.187	likely benign
REVEL	0.531	indeterminate
SaProt	LLR -5.34	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.54	unconstrained · MANE · 19 kb · p 2.1e-18 · regional, not allelic
Overall
CADD	23.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000763% European (non-Finnish) · 9/1,179,726 alleles

Filtering AF 0.000359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.000558% 9/1,613,024 alleles · very rare exomes 5/1,460,818 · genomes 4/152,206 · joint denominator

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.Cys593Arg
Coding: c.1777T>C
MANE Select: NM_003954
dbSNP: rs1480888701
Type: single nucleotide variant
Location: chr17:45271102 (GRCh38)
Gene constraint: LOEUF 0.263 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 61.00 · 8 PDB
Residue 593: the protein kinase domain; the 'interaction with zfp91' region

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-cys593arg (accessed [today's date]).

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