Is MAP4K2 p.Val678Ile (c.2032G>A) pathogenic?

MAP4K2 p.Val678Ile (c.2032G>A) is classified Uncertain significance in MAP4K2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-06). AlphaMissense: likely benign (0.1033); Very rare (popmax 0.00338%, amr).

How common is MAP4K2 p.Val678Ile (c.2032G>A) in the general population?

MAP4K2 p.Val678Ile (c.2032G>A) is very rare (popmax 0.00338%, amr) (gnomAD).

What do computational predictors say about MAP4K2 p.Val678Ile (c.2032G>A)?

AlphaMissense predicts likely benign (score 0.1033) — an in-silico prediction, not a clinical call.

MAP4K2 p.Val678Ile

c.2032G>A · rs376125345 · VCV3123084

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1033 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00338%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1033	likely benign
REVEL	0.056	moderately benign-leaning
SaProt	LLR -7.92	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.1	GERP 1.4, 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

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 0.00338% Admixed American · 2/59,094 alleles

Filtering AF 0.00115% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000973%

Overall 0.00174% 28/1,604,984 alleles · very rare exomes 26/1,452,760 · genomes 2/152,224 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00338%	29,547
Remaining individualsnot grpmax-eligible	0.00322%	31,029
East Asian	0.00224%	44,636
South Asian	0.00223%	44,759
European (non-Finnish)	0.00178%	56,025

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.Val678Ile
Coding: c.2032G>A
MANE Select: NM_004579
dbSNP: rs376125345
Type: single nucleotide variant
Location: chr11:64791969 (GRCh38)
Gene constraint: LOEUF 0.867 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.32
Residue 678: the cnh 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-val678ile (accessed [today's date]).

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