Is MAP3K1 p.Arg306Cys (c.916C>T) pathogenic?

MAP3K1 p.Arg306Cys (c.916C>T) is classified Likely benign in MAP3K1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-15). AlphaMissense: ambiguous (0.559); Very rare (popmax 0.00534%, afr); Associated with 46,XY sex reversal 6.

What condition is associated with MAP3K1 p.Arg306Cys (c.916C>T)?

MAP3K1 p.Arg306Cys (c.916C>T) is associated with 46,XY sex reversal 6 (ClinVar).

How common is MAP3K1 p.Arg306Cys (c.916C>T) in the general population?

MAP3K1 p.Arg306Cys (c.916C>T) is very rare (popmax 0.00534%, afr) (gnomAD).

What do computational predictors say about MAP3K1 p.Arg306Cys (c.916C>T)?

AlphaMissense predicts ambiguous (score 0.559) — an in-silico prediction, not a clinical call.

MAP3K1 p.Arg306Cys

c.916C>T · rs749900834 · VCV2203650

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.559 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00534%, afr)

Conditions

46,XY sex reversal 6

Computational evidence

Protein change
AlphaMissense	0.559	ambiguous
REVEL	0.35	indeterminate
SaProt	LLR -10.92	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.7, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 8,192 bp · p 0.028 · regional, not allelic
Overall
CADD	32.0	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 0.00534% African / African-American · 4/74,870 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00112% 18/1,613,914 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00534%	18,718
East Asian	0.00223%	44,880
South Asian	0.0011%	91,074
European (non-Finnish)	0.00102%	98,334

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.Arg306Cys
Coding: c.916C>T
MANE Select: NM_005921
dbSNP: rs749900834
Type: single nucleotide variant
Location: chr5:56864815 (GRCh38)
Gene constraint: LOEUF 0.355 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 59.80 · 1 PDB

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.Arg306His Conflicting classifications of pathogenicity ★ ⚠ same residue
MAP3K1 p.Arg306= Likely benign ★ 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

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-arg306cys (accessed [today's date]).

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