Is MAP4K2 p.Val116Ile (c.346G>A) pathogenic?

MAP4K2 p.Val116Ile (c.346G>A) is classified Uncertain significance in MAP4K2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-30). AlphaMissense: likely benign (0.1028); Ultra-rare (popmax 0.0395%, sas).

How common is MAP4K2 p.Val116Ile (c.346G>A) in the general population?

MAP4K2 p.Val116Ile (c.346G>A) is ultra-rare (popmax 0.0395%, sas) (gnomAD).

What do computational predictors say about MAP4K2 p.Val116Ile (c.346G>A)?

AlphaMissense predicts likely benign (score 0.1028) — an in-silico prediction, not a clinical call.

MAP4K2 p.Val116Ile

c.346G>A · VCV3542974

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1028 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0395%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1028	likely benign
REVEL	0.095	moderately benign-leaning
SaProt	LLR -6.96	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.7	GERP 1.5, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 13 kb · p 0.0094 · regional, not allelic
Overall
CADD	21.4	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 0.0395% South Asian · 36/91,026 alleles

Filtering AF 0.0293% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0258%

Overall 0.0128% 207/1,612,846 alleles · ultra-rare exomes 198/1,460,506 · genomes 9/152,340 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0395%	2,529
European (non-Finnish)	0.0133%	7,515
Admixed American	0.00833%	11,999
Remaining individualsnot grpmax-eligible	0.00801%	12,489
East Asian	0.00446%	22,438
African / African-American	0.00266%	37,528

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.Val116Ile
Coding: c.346G>A
MANE Select: NM_004579
Type: single nucleotide variant
Location: chr11:64802086 (GRCh38)
Gene constraint: LOEUF 0.867 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.32
Residue 116: 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-val116ile (accessed [today's date]).

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