Is MAP3K15 p.Leu734Phe (c.2200C>T) pathogenic?

MAP3K15 p.Leu734Phe (c.2200C>T) is classified Uncertain significance in MAP3K15 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-08). AlphaMissense: likely pathogenic (0.8492); Very rare (popmax 0.00225%, amr).

How common is MAP3K15 p.Leu734Phe (c.2200C>T) in the general population?

MAP3K15 p.Leu734Phe (c.2200C>T) is very rare (popmax 0.00225%, amr) (gnomAD).

What do computational predictors say about MAP3K15 p.Leu734Phe (c.2200C>T)?

AlphaMissense predicts likely pathogenic (score 0.8492) — an in-silico prediction, not a clinical call.

MAP3K15 p.Leu734Phe

c.2200C>T · rs2518568878 · VCV3122894

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8492 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00225%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.8492	likely pathogenic
REVEL	0.519	indeterminate
SaProt	LLR -11.79	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 2.7, phastCons 1
Regional constraint	o/e 1.15	unconstrained · MANE · 155 kb · p 7.9e-07 · regional, not allelic
Overall
CADD	26.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00225% Admixed American · 1/44,499 alleles

Overall 8.3e-05% 1/1,205,165 alleles · very rare exomes 1/1,091,493 · genomes 0/113,672 · joint denominator

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.Leu734Phe
Coding: c.2200C>T
MANE Select: NM_001001671
dbSNP: rs2518568878
Type: single nucleotide variant
Location: chrX:19392468 (GRCh38)
Structure: AlphaFold pLDDT 75.41 · 1 PDB
Residue 734: the protein kinase domain

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-leu734phe (accessed [today's date]).

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