Is MAP3K1 p.Gly254= (c.762C>T) pathogenic?

MAP3K1 p.Gly254= (c.762C>T) is classified Benign/Likely benign in MAP3K1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2023-12-07). Rare (popmax 0.501%, afr); Associated with 46,XY sex reversal 6.

What condition is associated with MAP3K1 p.Gly254= (c.762C>T)?

MAP3K1 p.Gly254= (c.762C>T) is associated with 46,XY sex reversal 6 (ClinVar).

How common is MAP3K1 p.Gly254= (c.762C>T) in the general population?

MAP3K1 p.Gly254= (c.762C>T) is rare (popmax 0.501%, afr) (gnomAD).

MAP3K1 p.Gly254=

c.762C>T · rs199726815 · VCV772571

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

rare (popmax 0.501%, 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	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.2	GERP -5.2
Overall
CADD	9.742	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.501% African / African-American · 376/75,046 alleles

Filtering AF 0.459% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.443%

Overall 0.0257% 414/1,613,862 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.501%	200
Admixed American	0.0367%	2,728
Remaining individualsnot grpmax-eligible	0.0176%	5,681
Middle Eastern	0.0165%	6,058
European (non-Finnish)	0.000339%	294,978

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.Gly254=
Coding: c.762C>T
MANE Select: NM_005921
dbSNP: rs199726815
Type: single nucleotide variant
Location: chr5:56859843 (GRCh38)
Gene constraint: LOEUF 0.355 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 59.80 · 1 PDB
Residue 254: the 'disordered' region

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.Gly254Ser Uncertain significance ★ ⚠ same residue
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

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-gly254 (accessed [today's date]).

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