Is MAP3K15 p.Val657= (c.1971C>T) pathogenic?

MAP3K15 p.Val657= (c.1971C>T) is classified Benign in MAP3K15 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-03-04). Low-frequency (popmax 1.32%, afr); Associated with MAP3K15-related disorder.

What condition is associated with MAP3K15 p.Val657= (c.1971C>T)?

MAP3K15 p.Val657= (c.1971C>T) is associated with MAP3K15-related disorder (ClinVar).

How common is MAP3K15 p.Val657= (c.1971C>T) in the general population?

MAP3K15 p.Val657= (c.1971C>T) is low-frequency (popmax 1.32%, afr) (gnomAD).

MAP3K15 p.Val657=

c.1971C>T · rs139556701 · VCV3033464

Benign No assertion criteria

Classification

Benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

low-frequency (popmax 1.32%, afr)

Conditions

MAP3K15-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.24	GERP -4.4, phastCons 0.029
Overall
CADD	1.243	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.32% African / African-American · 754/57,006 alleles

Filtering AF 1.24% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.21%

Overall 0.0733% 886/1,209,154 alleles · low-frequency exomes 452/1,097,824 · genomes 434/111,330 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.32%	76
Admixed American	0.118%	844
Remaining individualsnot grpmax-eligible	0.109%	916
Middle Eastern	0.023%	4,350
East Asian	0.00296%	33,751
European (non-Finnish)	0.00257%	38,910
South Asian	0.00176%	56,756

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.Val657=
Coding: c.1971C>T
MANE Select: NM_001001671
dbSNP: rs139556701
Type: single nucleotide variant
Location: chrX:19398321 (GRCh38)
Structure: AlphaFold pLDDT 75.41 · 1 PDB
Residue 657: the protein kinase domain

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

Disease context

MAP3K15-related disorder

Similar variants

MAP3K15 p.Ile295Ser Uncertain significance ★★ ⚠ same condition
MAP3K15 p.Leu154Phe Uncertain significance ★★ ⚠ same condition
MAP3K15 p.Thr1229Arg Uncertain significance ★★ ⚠ same condition
MAP3K15 p.Gln541Ter Uncertain significance same condition
MAP3K15 c.1440-1G>T Likely benign same condition
MAP3K15 c.719+9C>T Benign same condition
MAP3K15 p.Ala192Thr Benign same condition
MAP3K15 p.Ala264Val Likely benign 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/map3k15-p-val657 (accessed [today's date]).

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