Is MAP3K1 p.Leu764Arg (c.2291T>G) pathogenic?

MAP3K1 p.Leu764Arg (c.2291T>G) is classified Uncertain significance in MAP3K1 (ClinVar, Single submitter, 1 submitter; last evaluated 2016-06-06). AlphaMissense: likely pathogenic (0.9829); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with MAP3K1 p.Leu764Arg (c.2291T>G)?

MAP3K1 p.Leu764Arg (c.2291T>G) is associated with Inborn genetic diseases (ClinVar).

How common is MAP3K1 p.Leu764Arg (c.2291T>G) in the general population?

MAP3K1 p.Leu764Arg (c.2291T>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MAP3K1 p.Leu764Arg (c.2291T>G)?

AlphaMissense predicts likely pathogenic (score 0.9829) — an in-silico prediction, not a clinical call.

MAP3K1 p.Leu764Arg

c.2291T>G · rs1554035648 · VCV521104

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9829 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9829	likely pathogenic
REVEL	0.512	indeterminate
SaProt	LLR -16.99	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.7, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 11 kb · p 0.13 · regional, not allelic
Overall
CADD	26.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: MAP3K1
Protein: p.Leu764Arg
Coding: c.2291T>G
MANE Select: NM_005921
dbSNP: rs1554035648
Type: single nucleotide variant
Location: chr5:56881194 (GRCh38)
Gene constraint: LOEUF 0.355 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 59.80 · 1 PDB
Residue 764: an α-helix

Full MAP3K1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MAP3K1 p.Ala594Ser Uncertain significance ★★ ⚠ same condition
MAP3K1 p.Arg204Lys Uncertain significance ★★ ⚠ same condition
MAP3K1 p.Val1346Ile Uncertain significance ★★ ⚠ same condition
MAP3K1 p.Pro962= Benign/Likely benign ★★ same condition
MAP3K1 p.Leu189Gln Likely pathogenic ★ ⚠ same condition
MAP3K1 p.Ala1017Val Uncertain significance ★ ⚠ same condition
MAP3K1 p.Ala1327Pro Uncertain significance ★ ⚠ same condition
MAP3K1 p.Ala1402Gly Uncertain significance ★ ⚠ 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-leu764arg (accessed [today's date]).

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