Is MAP4K5 p.Arg87Trp (c.259C>T) pathogenic?

MAP4K5 p.Arg87Trp (c.259C>T) is classified Uncertain significance in MAP4K5 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-21). AlphaMissense: likely pathogenic (0.6231); Very rare (popmax 0.0049%, eas).

How common is MAP4K5 p.Arg87Trp (c.259C>T) in the general population?

MAP4K5 p.Arg87Trp (c.259C>T) is very rare (popmax 0.0049%, eas) (gnomAD).

What do computational predictors say about MAP4K5 p.Arg87Trp (c.259C>T)?

AlphaMissense predicts likely pathogenic (score 0.6231) — an in-silico prediction, not a clinical call.

MAP4K5 p.Arg87Trp

c.259C>T · VCV3870340

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6231 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0049%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.6231	likely pathogenic
REVEL	0.314	indeterminate
SaProt	LLR -14.45	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.85 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7	GERP 1.3, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 56 kb · p 0.63 · regional, not allelic
Overall
CADD	32.0	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

Grpmax group 0.0049% East Asian · 2/40,844 alleles

Filtering AF 0.00164% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0014%

Overall 0.00223% 34/1,526,606 alleles · very rare exomes 30/1,375,376 · genomes 4/151,230 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0049%	20,422
African / African-American	0.00279%	35,904
European (non-Finnish)	0.00239%	41,810
Admixed American	0.002%	50,018
Remaining individualsnot grpmax-eligible	0.00169%	59,136
Finnishnot grpmax-eligible	0.00168%	59,466

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: MAP4K5
Protein: p.Arg87Trp
Coding: c.259C>T
MANE Select: NM_006575
Type: single nucleotide variant
Location: chr14:50485641 (GRCh38)
Gene constraint: LOEUF 0.764 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.15
Residue 87: the protein kinase domain

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

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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-arg87trp (accessed [today's date]).

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