Is MAP4K2 p.Thr283Ala (c.847A>G) pathogenic?

MAP4K2 p.Thr283Ala (c.847A>G) is classified Uncertain significance in MAP4K2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-14). AlphaMissense: likely benign (0.0677); Ultra-rare (popmax 0.0217%, amr).

How common is MAP4K2 p.Thr283Ala (c.847A>G) in the general population?

MAP4K2 p.Thr283Ala (c.847A>G) is ultra-rare (popmax 0.0217%, amr) (gnomAD).

What do computational predictors say about MAP4K2 p.Thr283Ala (c.847A>G)?

AlphaMissense predicts likely benign (score 0.0677) — an in-silico prediction, not a clinical call.

MAP4K2 p.Thr283Ala

c.847A>G · VCV4051435

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0677 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0217%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0677	likely benign
REVEL	0.053	moderately benign-leaning
SaProt	LLR -9.73	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>G here scores Δ0.41 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.8	GERP 1.7, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 13 kb · p 0.0094 · regional, not allelic
Overall
CADD	22.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0217% Admixed American · 13/59,920 alleles

Filtering AF 0.0128% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0101%

Overall 0.000868% 14/1,613,070 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0217%	4,609
Remaining individualsnot grpmax-eligible	0.0016%	62,436

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: MAP4K2
Protein: p.Thr283Ala
Coding: c.847A>G
MANE Select: NM_004579
Type: single nucleotide variant
Location: chr11:64800177 (GRCh38)
Gene constraint: LOEUF 0.867 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.32

Full MAP4K2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MAP4K2 p.Ala120Ser Benign ★★ same type
MAP4K2 p.Asn606= Benign ★★ same type
MAP4K2 p.Ala183Asp Uncertain significance ★ ⚠ same type
MAP4K2 p.Ala184Ser Uncertain significance ★ ⚠ same type
MAP4K2 p.Ala405Thr Uncertain significance ★ ⚠ same type
MAP4K2 p.Ala487Thr Uncertain significance ★ ⚠ same type
MAP4K2 p.Ala790Asp Uncertain significance ★ ⚠ same type
MAP4K2 p.Ala806Val 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/map4k2-p-thr283ala (accessed [today's date]).

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