Is MAP4K1 p.Cys90Phe (c.269G>T) pathogenic?

MAP4K1 p.Cys90Phe (c.269G>T) is classified Uncertain significance in MAP4K1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-22). AlphaMissense: likely pathogenic (0.877); Very rare (popmax 0.00167%, amr).

How common is MAP4K1 p.Cys90Phe (c.269G>T) in the general population?

MAP4K1 p.Cys90Phe (c.269G>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about MAP4K1 p.Cys90Phe (c.269G>T)?

AlphaMissense predicts likely pathogenic (score 0.877) — an in-silico prediction, not a clinical call.

MAP4K1 p.Cys90Phe

c.269G>T · VCV3870301

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.877 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.877	likely pathogenic
REVEL	0.415	indeterminate
SaProt	LLR -13.21	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.3, phastCons 1
Regional constraint	o/e 0.57	unconstrained · MANE · 6,610 bp · p 3.4e-13 · regional, not allelic
Overall
CADD	28.1	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

Grpmax group 0.00167% Admixed American · 1/59,814 alleles

Overall 6.2e-05% 1/1,613,396 alleles · very rare exomes 0/1,461,262 · genomes 1/152,134 · joint denominator

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: MAP4K1
Protein: p.Cys90Phe
Coding: c.269G>T
MANE Select: NM_001042600
Type: single nucleotide variant
Location: chr19:38616239 (GRCh38)
Gene constraint: LOEUF 0.395 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 68.83 · 50 PDB
Residue 90: the protein kinase domain; a β-strand

Full MAP4K1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MAP4K1 p.Ala246Ser Uncertain significance ★ ⚠ same type
MAP4K1 p.Ala313Pro Uncertain significance ★ ⚠ same type
MAP4K1 p.Ala452Ser Uncertain significance ★ ⚠ same type
MAP4K1 p.Ala452Thr Uncertain significance ★ ⚠ same type
MAP4K1 p.Ala452Val Uncertain significance ★ ⚠ same type
MAP4K1 p.Ala485Ser Uncertain significance ★ ⚠ same type
MAP4K1 p.Ala609Val Uncertain significance ★ ⚠ same type
MAP4K1 p.Ala661Gly Uncertain significance ★ ⚠ 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/map4k1-p-cys90phe (accessed [today's date]).

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