Is MAP3K1 p.Leu760Phe (c.2278C>T) pathogenic?

MAP3K1 p.Leu760Phe (c.2278C>T) is classified Uncertain significance in MAP3K1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-22). AlphaMissense: likely pathogenic (0.6199); Absent from gnomAD v4.1.

How common is MAP3K1 p.Leu760Phe (c.2278C>T) in the general population?

MAP3K1 p.Leu760Phe (c.2278C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MAP3K1 p.Leu760Phe (c.2278C>T)?

AlphaMissense predicts likely pathogenic (score 0.6199) — an in-silico prediction, not a clinical call.

MAP3K1 p.Leu760Phe

c.2278C>T · VCV3337265

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6199 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6199	likely pathogenic
REVEL	0.201	benign-leaning
SaProt	LLR -7.76	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 2.7, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 11 kb · p 0.13 · regional, not allelic
Overall
CADD	21.4	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

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.Leu760Phe
Coding: c.2278C>T
MANE Select: NM_005921
Type: single nucleotide variant
Location: chr5:56881181 (GRCh38)
Gene constraint: LOEUF 0.355 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 59.80 · 1 PDB
Residue 760: an α-helix

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

Similar variants

MAP3K1 p.Arg186Gly Pathogenic/Likely pathogenic ★★ ⚠ same type
MAP3K1 p.Ala594Ser Uncertain significance ★★ ⚠ same type
MAP3K1 p.Arg204Lys Uncertain significance ★★ ⚠ same type
MAP3K1 p.Gln548Glu Uncertain significance ★★ ⚠ same type
MAP3K1 p.Val1346Ile Uncertain significance ★★ ⚠ same type
MAP3K1 c.1035+12C>T Likely benign ★★ same type
MAP3K1 c.1687-46C>G Benign ★★ same type
MAP3K1 c.2088-92C>T Benign ★★ same type

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-leu760phe (accessed [today's date]).

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