Is MAP3K1 p.Arg248Gln (c.743G>A) pathogenic?

MAP3K1 p.Arg248Gln (c.743G>A) is classified Likely benign in MAP3K1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-15). AlphaMissense: likely benign (0.1302); Rare (popmax 0.38%, mid); Associated with 46,XY sex reversal 6.

What condition is associated with MAP3K1 p.Arg248Gln (c.743G>A)?

MAP3K1 p.Arg248Gln (c.743G>A) is associated with 46,XY sex reversal 6 (ClinVar).

How common is MAP3K1 p.Arg248Gln (c.743G>A) in the general population?

MAP3K1 p.Arg248Gln (c.743G>A) is rare (popmax 0.38%, mid) (gnomAD).

What do computational predictors say about MAP3K1 p.Arg248Gln (c.743G>A)?

AlphaMissense predicts likely benign (score 0.1302) — an in-silico prediction, not a clinical call.

MAP3K1 p.Arg248Gln

c.743G>A · rs201579608 · VCV1147868

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1302 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.38%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

46,XY sex reversal 6

Computational evidence

Protein change
AlphaMissense	0.1302	likely benign
REVEL	0.307	indeterminate
SaProt	LLR -7.97	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.6, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 8,192 bp · p 0.028 · regional, not allelic
Overall
CADD	23.8	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 0.38% Middle Eastern · 23/6,058 alleles

Filtering AF 0.259% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.22%

Overall 0.0166% 268/1,613,870 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.38%	263
East Asian	0.0535%	1,869
Remaining individualsnot grpmax-eligible	0.0272%	3,676
Admixed American	0.0183%	5,454
European (non-Finnish)	0.0147%	6,820
African / African-American	0.0147%	6,822
South Asian	0.00989%	10,113

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.Arg248Gln
Coding: c.743G>A
MANE Select: NM_005921
dbSNP: rs201579608
Type: single nucleotide variant
Location: chr5:56859824 (GRCh38)
Gene constraint: LOEUF 0.355 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 59.80 · 1 PDB
Residue 248: 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.Arg248= 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
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-arg248gln (accessed [today's date]).

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