Is MAP3K3 p.Arg375Ser (c.1125G>T) pathogenic?

MAP3K3 p.Arg375Ser (c.1125G>T) is classified Uncertain significance in MAP3K3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-11). AlphaMissense: ambiguous (0.3861); Very rare (popmax 0.00314%, nfe).

How common is MAP3K3 p.Arg375Ser (c.1125G>T) in the general population?

MAP3K3 p.Arg375Ser (c.1125G>T) is very rare (popmax 0.00314%, nfe) (gnomAD).

What do computational predictors say about MAP3K3 p.Arg375Ser (c.1125G>T)?

AlphaMissense predicts ambiguous (score 0.3861) — an in-silico prediction, not a clinical call.

MAP3K3 p.Arg375Ser

c.1125G>T · VCV4279713

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3861 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00314%, nfe)

Computational evidence

Protein change
AlphaMissense	0.3861	ambiguous
REVEL	0.32	indeterminate
SaProt	LLR -5.57	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.9	GERP 0.83, phastCons 1
Regional constraint	o/e 0.62	unconstrained · MANE · 12 kb · p 1.9e-20 · regional, not allelic
Overall
CADD	23.3	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00314% European (non-Finnish) · 37/1,180,036 alleles

Filtering AF 0.00231% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00202%

Overall 0.00235% 38/1,614,022 alleles · very rare exomes 33/1,461,848 · genomes 5/152,174 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00314%	31,893
Remaining individualsnot grpmax-eligible	0.0016%	62,486

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: MAP3K3
Protein: p.Arg375Ser
Coding: c.1125G>T
MANE Select: NM_002401
Type: single nucleotide variant
Location: chr17:63690325 (GRCh38)
Gene constraint: LOEUF 0.209 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 67.20 · 6 PDB
Residue 375: the protein kinase domain; a binding site

Full MAP3K3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MAP3K3 p.Ile441Met Pathogenic/Likely pathogenic ★★ same type
MAP3K3 p.His133Tyr Uncertain significance ★★ ⚠ same type
MAP3K3 p.Met524Val Uncertain significance ★★ ⚠ same type
MAP3K3 c.126+67G>T Benign ★★ same type
MAP3K3 c.1475-146T>C Benign ★★ same type
MAP3K3 c.168-35A>G Benign ★★ same type
MAP3K3 c.268-98T>C Benign ★★ same type
MAP3K3 c.382-260A>G Benign ★★ same type

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/map3k3-p-arg375ser (accessed [today's date]).

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