Is MAP3K1 p.Arg757Cys (c.2269C>T) pathogenic?

MAP3K1 p.Arg757Cys (c.2269C>T) is classified Uncertain significance in MAP3K1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-23). AlphaMissense: ambiguous (0.514); Very rare (popmax 0.00935%, afr); Associated with 46,XY sex reversal 6.

What condition is associated with MAP3K1 p.Arg757Cys (c.2269C>T)?

MAP3K1 p.Arg757Cys (c.2269C>T) is associated with 46,XY sex reversal 6 (ClinVar).

How common is MAP3K1 p.Arg757Cys (c.2269C>T) in the general population?

MAP3K1 p.Arg757Cys (c.2269C>T) is very rare (popmax 0.00935%, afr) (gnomAD).

What do computational predictors say about MAP3K1 p.Arg757Cys (c.2269C>T)?

AlphaMissense predicts ambiguous (score 0.514) — an in-silico prediction, not a clinical call.

MAP3K1 p.Arg757Cys

c.2269C>T · VCV4801744

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.514 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00935%, afr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

46,XY sex reversal 6

Computational evidence

Protein change
AlphaMissense	0.514	ambiguous
REVEL	0.257	benign-leaning
SaProt	LLR -10.50	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.20 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.7	GERP 2.7, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 11 kb · p 0.13 · regional, not allelic
Overall
CADD	27.5	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 0.00935% African / African-American · 7/74,842 alleles

Filtering AF 0.00438% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00309%

Overall 0.0026% 42/1,613,410 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00935%	10,692
Admixed American	0.00834%	11,987
European (non-Finnish)	0.00246%	40,682
Remaining individualsnot grpmax-eligible	0.0016%	62,462

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.Arg757Cys
Coding: c.2269C>T
MANE Select: NM_005921
Type: single nucleotide variant
Location: chr5:56881172 (GRCh38)
Gene constraint: LOEUF 0.355 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 59.80 · 1 PDB
Residue 757: an α-helix

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-arg757cys (accessed [today's date]).

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