Is MAP4K5 p.Trp91Cys (c.273G>C) pathogenic?

MAP4K5 p.Trp91Cys (c.273G>C) is classified Uncertain significance in MAP4K5 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-01). AlphaMissense: likely pathogenic (0.9976); Absent from gnomAD v4.1.

How common is MAP4K5 p.Trp91Cys (c.273G>C) in the general population?

MAP4K5 p.Trp91Cys (c.273G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MAP4K5 p.Trp91Cys (c.273G>C)?

AlphaMissense predicts likely pathogenic (score 0.9976) — an in-silico prediction, not a clinical call.

MAP4K5 p.Trp91Cys

c.273G>C · VCV3543018

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9976 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.9976	likely pathogenic
REVEL	0.604	indeterminate
SaProt	LLR -11.16	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 7.6	GERP 2.1, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 56 kb · p 0.63 · regional, not allelic
Overall
CADD	33.0	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: MAP4K5
Protein: p.Trp91Cys
Coding: c.273G>C
MANE Select: NM_006575
Type: single nucleotide variant
Location: chr14:50485627 (GRCh38)
Gene constraint: LOEUF 0.764 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.15
Residue 91: the protein kinase domain

Full MAP4K5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MAP4K5 p.Val739Ile Uncertain significance ★★ ⚠ same type
ATL1 c.-140+55A>T Benign ★★ same type
MAP4K5 p.Val731= Benign ★★ same type
MAP4K5 c.1709-2A>T Uncertain significance ★ same type
MAP4K5 p.Ala278Thr Uncertain significance ★ ⚠ same type
MAP4K5 p.Ala328Val Uncertain significance ★ ⚠ same type
MAP4K5 p.Ala37Val Uncertain significance ★ ⚠ same type
MAP4K5 p.Ala425Thr 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/map4k5-p-trp91cys (accessed [today's date]).

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