Is MAP2K3 p.Pro40Thr (c.118C>A) pathogenic?

MAP2K3 p.Pro40Thr (c.118C>A) is classified Benign in MAP2K3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2018-06-04). AlphaMissense: ambiguous (0.3718); Common (popmax 50%, mid) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about MAP2K3 p.Pro40Thr (c.118C>A)?

AlphaMissense predicts ambiguous (score 0.3718) — an in-silico prediction, not a clinical call.

MAP2K3 p.Pro40Thr

Q: How common is MAP2K3 p.Pro40Thr (c.118C>A) in the general population?

MAP2K3 p.Pro40Thr (c.118C>A) is common (popmax 50%, mid) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.118C>A · rs33911218 · VCV768842

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3718 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 50%, mid) — too common for a highly-penetrant pathogenic allele

Computational evidence

Protein change
AlphaMissense	0.3718	ambiguous
REVEL	0.357	indeterminate
SaProt	LLR -6.54	tolerated
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4	GERP 0.19, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 20 kb · p 0.26 · regional, not allelic
Overall
CADD	24.8	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 50% Middle Eastern · 3,030/6,060 alleles

Filtering AF 49.9% ClinGen BA1/BS1 input FAF95, joint · FAF99 49.8%

Overall 50% 805,424/1,611,164 alleles · common exomes 729,289/1,458,886 · genomes 76,135/152,278 · joint denominator

Ancestry group	Frequency	1 in
East Asian	50%	2
Finnishnot grpmax-eligible	50%	2
Amishnot grpmax-eligible	50%	2
Middle Easterngrpmax	50%	2
Remaining individualsnot grpmax-eligible	50%	2
Admixed American	50%	2
African / African-American	50%	2
South Asian	50%	2
Ashkenazi Jewishnot grpmax-eligible	50%	2
European (non-Finnish)	50%	2

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: MAP2K3
Protein: p.Pro40Thr
Coding: c.118C>A
MANE Select: NM_145109
dbSNP: rs33911218
Type: single nucleotide variant
Location: chr17:21298879 (GRCh38)
Gene constraint: LOEUF 0.993 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.13
Residue 40: a UniProt-annotated variant site (in); the 'disordered' region

Full MAP2K3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MAP2K3 p.Leu215Trp Uncertain significance ★★ ⚠ same type
MAP2K3 c.568+10C>T Benign ★★ same type
MAP2K3 p.Ala220= Benign ★★ same type
MAP2K3 p.Ala225= Likely benign ★★ same type
MAP2K3 p.Leu25= Benign ★★ same type
MAP2K3 p.Leu319= Likely benign ★★ same type
MAP2K3 p.Ser286= Likely benign ★★ same type
MAP2K3 p.Thr39Ile Likely 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/map2k3-p-pro40thr (accessed [today's date]).

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