Is MAPK8IP3 p.Ser751Thr (c.2252G>C) pathogenic?

MAPK8IP3 p.Ser751Thr (c.2252G>C) is classified Likely benign in MAPK8IP3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-09-01). AlphaMissense: likely benign (0.0733); Very rare (popmax 0.00119%, nfe); Associated with Inborn genetic diseases.

What condition is associated with MAPK8IP3 p.Ser751Thr (c.2252G>C)?

MAPK8IP3 p.Ser751Thr (c.2252G>C) is associated with Inborn genetic diseases (ClinVar).

How common is MAPK8IP3 p.Ser751Thr (c.2252G>C) in the general population?

MAPK8IP3 p.Ser751Thr (c.2252G>C) is very rare (popmax 0.00119%, nfe) (gnomAD).

What do computational predictors say about MAPK8IP3 p.Ser751Thr (c.2252G>C)?

AlphaMissense predicts likely benign (score 0.0733) — an in-silico prediction, not a clinical call.

MAPK8IP3 p.Ser751Thr

c.2252G>C · rs201443607 · VCV3123324

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0733 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00119%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0733	likely benign
REVEL	0.148	moderately benign-leaning
SaProt	LLR -7.20	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 8.4	GERP 2.1, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 5,099 bp · p 0.00099 · regional, not allelic
Overall
CADD	20.7	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 S750T vs ClinVar S751T) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00119% European (non-Finnish) · 14/1,178,798 alleles

Filtering AF 0.000689% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000539%

Overall 0.00504% 81/1,607,884 alleles · very rare exomes 75/1,455,646 · genomes 6/152,238 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.193%	517
Remaining individualsnot grpmax-eligible	0.0161%	6,216
European (non-Finnish)grpmax	0.00119%	84,200

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ser751Thr
Coding: c.2252G>C
MANE Select: NM_001318852
dbSNP: rs201443607
Type: single nucleotide variant
Location: chr16:1764431 (GRCh38)
Gene constraint: LOEUF 0.407 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 63.19 · 5 PDB
Residue 750 UniProt numbering: 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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MAPK8IP3 p.Arg579Cys Pathogenic/Likely pathogenic ★★ same condition
MAPK8IP3 c.1898+5G>A Uncertain significance ★★ same condition
MAPK8IP3 p.Ala883Thr Uncertain significance ★★ ⚠ same condition
MAPK8IP3 p.Arg1012Cys Uncertain significance ★★ ⚠ same condition
MAPK8IP3 p.Arg1187Gln Uncertain significance ★★ ⚠ same condition
MAPK8IP3 p.Arg308Cys Uncertain significance ★★ ⚠ same condition
MAPK8IP3 p.Arg310Trp Uncertain significance ★★ ⚠ same condition
MAPK8IP3 p.Arg612Cys 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/mapk8ip3-p-ser751thr (accessed [today's date]).

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