Is MAP4K2 p.Asp53Glu (c.159C>A) pathogenic?

MAP4K2 p.Asp53Glu (c.159C>A) is classified Uncertain significance in MAP4K2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-01). AlphaMissense: likely pathogenic (0.7633); Ultra-rare (popmax 0.0182%, nfe).

How common is MAP4K2 p.Asp53Glu (c.159C>A) in the general population?

MAP4K2 p.Asp53Glu (c.159C>A) is ultra-rare (popmax 0.0182%, nfe) (gnomAD).

What do computational predictors say about MAP4K2 p.Asp53Glu (c.159C>A)?

AlphaMissense predicts likely pathogenic (score 0.7633) — an in-silico prediction, not a clinical call.

MAP4K2 p.Asp53Glu

c.159C>A · rs375333253 · VCV2461114

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7633 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0182%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7633	likely pathogenic
REVEL	0.129	moderately benign-leaning
SaProt	LLR -7.54	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>A here scores Δ0.44 · evaluated, not missing
Constraint at this position
Conservation	phyloP 4.1	GERP -2.4, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 13 kb · p 0.0094 · regional, not allelic
Overall
CADD	22.2	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

Grpmax group 0.0182% European (non-Finnish) · 215/1,179,312 alleles

Filtering AF 0.0162% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0154%

Overall 0.0136% 219/1,612,124 alleles · ultra-rare exomes 213/1,460,014 · genomes 6/152,110 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0182%	5,485
African / African-American	0.00401%	24,966
Remaining individualsnot grpmax-eligible	0.0016%	62,418

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.Asp53Glu
Coding: c.159C>A
MANE Select: NM_004579
dbSNP: rs375333253
Type: single nucleotide variant
Location: chr11:64802649 (GRCh38)
Gene constraint: LOEUF 0.867 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.32
Residue 53: the protein kinase domain

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-asp53glu (accessed [today's date]).

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