Is MAP3K1 p.Arg162His (c.485G>A) pathogenic?

MAP3K1 p.Arg162His (c.485G>A) is classified Uncertain significance in MAP3K1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-10). AlphaMissense: likely benign (0.3118); Ultra-rare (popmax 0.0165%, mid); Associated with 46,XY sex reversal 6.

What condition is associated with MAP3K1 p.Arg162His (c.485G>A)?

MAP3K1 p.Arg162His (c.485G>A) is associated with 46,XY sex reversal 6 (ClinVar).

How common is MAP3K1 p.Arg162His (c.485G>A) in the general population?

MAP3K1 p.Arg162His (c.485G>A) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about MAP3K1 p.Arg162His (c.485G>A)?

AlphaMissense predicts likely benign (score 0.3118) — an in-silico prediction, not a clinical call.

MAP3K1 p.Arg162His

c.485G>A · VCV3657507

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3118 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

46,XY sex reversal 6

Computational evidence

Protein change
AlphaMissense	0.3118	likely benign
REVEL	0.216	benign-leaning
SaProt	LLR -7.88	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.4	GERP 1.7, phastCons 1
Regional constraint	o/e 1.31	unconstrained · MANE · 41 kb · p 2.7e-07 · regional, not allelic
Overall
CADD	25.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,076 alleles

Filtering AF 0.00323% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00207%

Overall 0.00292% 47/1,612,268 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,076
Admixed American	0.00834%	11,992
African / African-American	0.00668%	14,963
European (non-Finnish)	0.00272%	36,832
South Asian	0.0022%	45,526
Remaining individualsnot grpmax-eligible	0.0016%	62,412
Finnishnot grpmax-eligible	0.00156%	63,980

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.Arg162His
Coding: c.485G>A
MANE Select: NM_005921
Type: single nucleotide variant
Location: chr5:56856602 (GRCh38)
Gene constraint: LOEUF 0.355 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 59.80 · 1 PDB
Residue 162: 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.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-arg162his (accessed [today's date]).

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