Is MAP4K4 p.Met72Val (c.214A>G) pathogenic?

MAP4K4 p.Met72Val (c.214A>G) is classified Uncertain significance in MAP4K4 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-30). AlphaMissense: likely pathogenic (0.657); Very rare (popmax 0.00134%, afr).

How common is MAP4K4 p.Met72Val (c.214A>G) in the general population?

MAP4K4 p.Met72Val (c.214A>G) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about MAP4K4 p.Met72Val (c.214A>G)?

AlphaMissense predicts likely pathogenic (score 0.657) — an in-silico prediction, not a clinical call.

MAP4K4 p.Met72Val

c.214A>G · VCV4975882

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.657 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.657	likely pathogenic
REVEL	0.445	indeterminate
SaProt	LLR -12.31	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP 2.3, phastCons 1
Regional constraint	o/e 0.39	unconstrained · MANE · 158 kb · p 1.1e-42 · regional, not allelic
Overall
CADD	24.1	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 0.00134% African / African-American · 1/74,804 alleles

Overall 0.000124% 2/1,607,420 alleles · very rare exomes 1/1,455,240 · genomes 1/152,180 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00134%	74,804
European (non-Finnish)	8.5e-05%	1,176,287

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: MAP4K4
Protein: p.Met72Val
Coding: c.214A>G
MANE Select: NM_001395002
Type: single nucleotide variant
Location: chr2:101823961 (GRCh38)
Gene constraint: LOEUF 0.308 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 66.47 · 19 PDB
Residue 72: the protein kinase domain; an α-helix

Full MAP4K4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MAP4K4 p.Arg1329Ter Pathogenic/Likely pathogenic ★★ same type
MAP4K4 p.Ala491Pro Uncertain significance ★★ ⚠ same type
MAP4K4 p.Arg1135Cys Uncertain significance ★★ ⚠ same type
MAP4K4 p.Leu742Pro Uncertain significance ★★ ⚠ same type
MAP4K4 p.Ser758Phe Uncertain significance ★★ ⚠ same type
MAP4K4 c.1022+125A>G Benign ★★ same type
MAP4K4 c.123+57A>G Benign ★★ same type
MAP4K4 c.1234-81C>G Benign ★★ 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/map4k4-p-met72val (accessed [today's date]).

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