Is MAP3K14 p.Arg910His (c.2729G>A) pathogenic?

MAP3K14 p.Arg910His (c.2729G>A) is classified Uncertain significance in MAP3K14 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-27). AlphaMissense: likely benign (0.0644); Very rare (popmax 0.00223%, eas); Associated with NIK deficiency.

What condition is associated with MAP3K14 p.Arg910His (c.2729G>A)?

MAP3K14 p.Arg910His (c.2729G>A) is associated with NIK deficiency (ClinVar).

How common is MAP3K14 p.Arg910His (c.2729G>A) in the general population?

MAP3K14 p.Arg910His (c.2729G>A) is very rare (popmax 0.00223%, eas) (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.Arg910His (c.2729G>A)?

AlphaMissense predicts likely benign (score 0.0644) — an in-silico prediction, not a clinical call.

MAP3K14 p.Arg910His

c.2729G>A · rs367798756 · VCV933453

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0644 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

NIK deficiency

Computational evidence

Protein change
AlphaMissense	0.0644	likely benign
REVEL	0.236	benign-leaning
SaProt	LLR -6.04	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.38	GERP -2.8
Regional constraint	o/e 0.59	unconstrained · MANE · 2,546 bp · p 1.1e-09 · regional, not allelic
Overall
CADD	15.85	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 0.00223% East Asian · 1/44,884 alleles

Filtering AF 0.00114% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000971%

Overall 0.00155% 25/1,613,252 alleles · very rare exomes 24/1,461,048 · genomes 1/152,204 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,884
European (non-Finnish)	0.00178%	56,176
Admixed American	0.00167%	59,920
Remaining individualsnot grpmax-eligible	0.0016%	62,450
South Asian	0.0011%	90,924

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.Arg910His
Coding: c.2729G>A
MANE Select: NM_003954
dbSNP: rs367798756
Type: single nucleotide variant
Location: chr17:45264751 (GRCh38)
Gene constraint: LOEUF 0.263 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 61.00 · 8 PDB

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-arg910his (accessed [today's date]).

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