Is MAP4K2 p.Ala183Asp (c.548C>A) pathogenic?

MAP4K2 p.Ala183Asp (c.548C>A) is classified Uncertain significance in MAP4K2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-29). AlphaMissense: likely pathogenic (0.9994); Very rare (popmax 0.00568%, nfe).

How common is MAP4K2 p.Ala183Asp (c.548C>A) in the general population?

MAP4K2 p.Ala183Asp (c.548C>A) is very rare (popmax 0.00568%, nfe) (gnomAD).

What do computational predictors say about MAP4K2 p.Ala183Asp (c.548C>A)?

AlphaMissense predicts likely pathogenic (score 0.9994) — an in-silico prediction, not a clinical call.

MAP4K2 p.Ala183Asp

c.548C>A · VCV4549563

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9994 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00568%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9994	likely pathogenic · top 1% in MAP4K2
REVEL	0.399	indeterminate
SaProt	LLR -14.21	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 13 kb · p 0.0094 · regional, not allelic
Overall
CADD	31.0	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 0.00568% European (non-Finnish) · 67/1,180,000 alleles

Filtering AF 0.00453% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00417%

Overall 0.0044% 71/1,613,784 alleles · very rare exomes 68/1,461,624 · genomes 3/152,160 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00568%	17,612
Remaining individualsnot grpmax-eligible	0.0048%	20,828
African / African-American	0.00133%	74,916

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.Ala183Asp
Coding: c.548C>A
MANE Select: NM_004579
Type: single nucleotide variant
Location: chr11:64801014 (GRCh38)
Gene constraint: LOEUF 0.867 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.32
Residue 183: 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.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
MAP4K2 p.Arg111Gln 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-ala183asp (accessed [today's date]).

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