Is MAPK8IP3 p.Thr754Ala (c.2260A>G) pathogenic?

MAPK8IP3 p.Thr754Ala (c.2260A>G) is classified Benign in MAPK8IP3 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2021-07-14). AlphaMissense: likely benign (0.0578); Common (popmax 36%, afr) — too common for a highly-penetrant pathogenic allele; Associated with neurodevelopmental disorder with or without variable brain abnormalities; NEDBA.

What condition is associated with MAPK8IP3 p.Thr754Ala (c.2260A>G)?

MAPK8IP3 p.Thr754Ala (c.2260A>G) is associated with neurodevelopmental disorder with or without variable brain abnormalities; NEDBA (ClinVar).

What do computational predictors say about MAPK8IP3 p.Thr754Ala (c.2260A>G)?

AlphaMissense predicts likely benign (score 0.0578) — an in-silico prediction, not a clinical call.

MAPK8IP3 p.Thr754Ala

Q: How common is MAPK8IP3 p.Thr754Ala (c.2260A>G) in the general population?

MAPK8IP3 p.Thr754Ala (c.2260A>G) is common (popmax 36%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.2260A>G · rs2294619 · VCV1185436

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0578 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 36%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neurodevelopmental disorder with or without variable brain abnormalities; NEDBA

Computational evidence

Protein change
AlphaMissense	0.0578	likely benign
REVEL	0.07	moderately benign-leaning
SaProt	LLR -6.15	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.28	GERP -4.2
Regional constraint	o/e 0.88	unconstrained · MANE · 5,099 bp · p 0.00099 · regional, not allelic
Overall
CADD	0.174	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM T753A vs ClinVar T754A) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 36% African / African-American · 26,957/74,886 alleles

Filtering AF 35.6% ClinGen BA1/BS1 input FAF95, joint · FAF99 35.5%

Overall 21.3% 342,117/1,607,070 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	36%	3
Admixed American	30.4%	3
South Asian	30%	3
Finnishnot grpmax-eligible	28.7%	3
East Asian	26.8%	4
Remaining individualsnot grpmax-eligible	22.3%	4
Middle Eastern	21.9%	5
European (non-Finnish)	18.6%	5
Ashkenazi Jewishnot grpmax-eligible	18.4%	5
Amishnot grpmax-eligible	18.2%	5

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: MAPK8IP3
Protein: p.Thr754Ala
Coding: c.2260A>G
MANE Select: NM_001318852
dbSNP: rs2294619
Type: single nucleotide variant
Location: chr16:1764439 (GRCh38)
Gene constraint: LOEUF 0.407 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 63.19 · 5 PDB
Residue 754: a UniProt-annotated variant site (in nedba); the 'disordered' region

Full MAPK8IP3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

neurodevelopmental disorder with or without variable brain abnormalities; NEDBA — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MAPK8IP3 p.Thr754Met Uncertain significance ★★ ⚠ same residue
MAPK8IP3 p.Arg1147Cys Pathogenic/Likely pathogenic ★★ same condition
MAPK8IP3 p.Arg579Cys Pathogenic/Likely pathogenic ★★ same condition
MAPK8IP3 p.Gln468Ter Pathogenic/Likely pathogenic ★★ same condition
MAPK8IP3 p.Glu27Ter Likely pathogenic ★★ same condition
MAPK8IP3 p.Glu462Gly Likely pathogenic ★★ same condition
MAPK8IP3 p.Leu445Pro Likely pathogenic ★★ same condition
MAPK8IP3 p.Tyr37Ter Likely pathogenic ★★ 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/mapk8ip3-p-thr754ala (accessed [today's date]).

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