Is MAP3K1 p.Leu1376= (c.4128A>C) pathogenic?

MAP3K1 p.Leu1376= (c.4128A>C) is classified Likely benign in MAP3K1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-15). Ultra-rare (popmax 0.048%, afr); Associated with 46,XY sex reversal 6.

What condition is associated with MAP3K1 p.Leu1376= (c.4128A>C)?

MAP3K1 p.Leu1376= (c.4128A>C) is associated with 46,XY sex reversal 6 (ClinVar).

How common is MAP3K1 p.Leu1376= (c.4128A>C) in the general population?

MAP3K1 p.Leu1376= (c.4128A>C) is ultra-rare (popmax 0.048%, afr) (gnomAD).

MAP3K1 p.Leu1376=

c.4128A>C · rs113150610 · VCV1140005

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.048%, afr)

Conditions

46,XY sex reversal 6

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>T here scores Δ0.45 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.69	GERP -5.2, phastCons 0.98
Overall
CADD	8.213	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.048% African / African-American · 36/75,048 alleles

Filtering AF 0.0356% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0313%

Overall 0.00483% 78/1,614,170 alleles · ultra-rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0672%	1,488
African / African-Americangrpmax	0.048%	2,085

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: MAP3K1
Protein: p.Leu1376=
Coding: c.4128A>C
MANE Select: NM_005921
dbSNP: rs113150610
Type: single nucleotide variant
Location: chr5:56887391 (GRCh38)
Gene constraint: LOEUF 0.355 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 59.80 · 1 PDB
Residue 1376: the protein kinase domain

Full MAP3K1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

46,XY sex reversal 6 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MAP3K1 p.Arg186Gly Pathogenic/Likely pathogenic ★★ ⚠ same condition
MAP3K1 p.Ala594Ser Uncertain significance ★★ ⚠ same condition
MAP3K1 p.Arg204Lys Uncertain significance ★★ ⚠ same condition
MAP3K1 p.Gln548Glu Uncertain significance ★★ ⚠ same condition
MAP3K1 c.1035+12C>T Likely benign ★★ same condition
MAP3K1 c.1687-46C>G Benign ★★ same condition
MAP3K1 c.2179+16T>G Benign/Likely benign ★★ same condition
MAP3K1 c.3820-11A>G 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/map3k1-p-leu1376 (accessed [today's date]).

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