Is MAP3K1 p.Phe1322Val (c.3964T>G) pathogenic?

MAP3K1 p.Phe1322Val (c.3964T>G) is classified Likely pathogenic in MAP3K1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-19). AlphaMissense: likely pathogenic (0.9626); Very rare (popmax 0.00751%, nfe); Associated with 46,XY sex reversal 6.

What condition is associated with MAP3K1 p.Phe1322Val (c.3964T>G)?

MAP3K1 p.Phe1322Val (c.3964T>G) is associated with 46,XY sex reversal 6 (ClinVar).

How common is MAP3K1 p.Phe1322Val (c.3964T>G) in the general population?

MAP3K1 p.Phe1322Val (c.3964T>G) is very rare (popmax 0.00751%, nfe) (gnomAD).

What do computational predictors say about MAP3K1 p.Phe1322Val (c.3964T>G)?

AlphaMissense predicts likely pathogenic (score 0.9626) — an in-silico prediction, not a clinical call.

MAP3K1 p.Phe1322Val

c.3964T>G · rs2530964031 · VCV2507001

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9626 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00751%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

46,XY sex reversal 6

Computational evidence

Protein change
AlphaMissense	0.9626	likely pathogenic ✓ concordant with ClinVar
REVEL	0.458	indeterminate
SaProt	LLR -9.93	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.2, phastCons 1
Regional constraint	o/e 0.51	unconstrained · MANE · 10 kb · p 1.5e-18 · regional, not allelic
Overall
CADD	27.7	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 0.00751% European (non-Finnish) · 88/1,171,314 alleles

Filtering AF 0.00619% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00577%

Overall 0.00586% 94/1,604,120 alleles · very rare exomes 94/1,451,854 · genomes 0/152,266 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00751%	13,310
Remaining individualsnot grpmax-eligible	0.00644%	15,525
East Asian	0.00224%	44,688
African / African-American	0.00134%	74,872

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.Phe1322Val
Coding: c.3964T>G
MANE Select: NM_005921
dbSNP: rs2530964031
Type: single nucleotide variant
Location: chr5:56884808 (GRCh38)
Gene constraint: LOEUF 0.355 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 59.80 · 1 PDB
Residue 1322: the protein kinase domain

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-phe1322val (accessed [today's date]).

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