Is MAP3K15 p.Arg84Pro (c.251G>C) pathogenic?

MAP3K15 p.Arg84Pro (c.251G>C) is classified Uncertain significance in MAP3K15 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-13). AlphaMissense: likely pathogenic (0.7889); Ultra-rare (popmax 0.0331%, mid).

How common is MAP3K15 p.Arg84Pro (c.251G>C) in the general population?

MAP3K15 p.Arg84Pro (c.251G>C) is ultra-rare (popmax 0.0331%, mid) (gnomAD).

What do computational predictors say about MAP3K15 p.Arg84Pro (c.251G>C)?

AlphaMissense predicts likely pathogenic (score 0.7889) — an in-silico prediction, not a clinical call.

MAP3K15 p.Arg84Pro

c.251G>C · rs754707908 · VCV2236543

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7889 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0331%, mid)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7889	likely pathogenic
REVEL	0.094	moderately benign-leaning
SaProt	LLR -10.98	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.86	GERP -3.4
Regional constraint	o/e 1.15	unconstrained · MANE · 155 kb · p 7.9e-07 · regional, not allelic
Overall
CADD	15.66	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 0.0331% Middle Eastern · 1/3,017 alleles

Filtering AF 0.00985% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0073%

Overall 0.00789% 86/1,089,849 alleles · ultra-rare exomes 80/983,118 · genomes 6/106,731 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0331%	3,017
South Asian	0.0189%	5,296
European (non-Finnish)	0.0087%	11,492
Remaining individualsnot grpmax-eligible	0.00469%	21,305
East Asian	0.00382%	26,167

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: MAP3K15
Protein: p.Arg84Pro
Coding: c.251G>C
MANE Select: NM_001001671
dbSNP: rs754707908
Type: single nucleotide variant
Location: chrX:19515011 (GRCh38)
Structure: AlphaFold pLDDT 75.41 · 1 PDB

Full MAP3K15 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MAP3K15 p.Ala859Thr Uncertain significance ★★ ⚠ same type
MAP3K15 p.Ile295Ser Uncertain significance ★★ ⚠ same type
MAP3K15 p.Leu154Phe Uncertain significance ★★ ⚠ same type
MAP3K15 p.Thr1229Arg Uncertain significance ★★ ⚠ same type
MAP3K15 p.Ser199Asn Benign ★★ same type
MAP3K15 p.Val455Ile Likely benign ★★ same type
PDHA1 c.*1013C>A Benign ★★ same type
PDHA1 c.*1059G>A 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/map3k15-p-arg84pro (accessed [today's date]).

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