Is MAP3K5 p.Ile708Val (c.2122A>G) pathogenic?

MAP3K5 p.Ile708Val (c.2122A>G) is classified Uncertain significance in MAP3K5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-19). AlphaMissense: likely benign (0.1997); Rare (popmax 0.667%, afr).

How common is MAP3K5 p.Ile708Val (c.2122A>G) in the general population?

MAP3K5 p.Ile708Val (c.2122A>G) is rare (popmax 0.667%, afr) (gnomAD).

What do computational predictors say about MAP3K5 p.Ile708Val (c.2122A>G)?

AlphaMissense predicts likely benign (score 0.1997) — an in-silico prediction, not a clinical call.

MAP3K5 p.Ile708Val

c.2122A>G · VCV4103380

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1997 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.667%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1997	likely benign
REVEL	0.155	moderately benign-leaning
SaProt	LLR -7.49	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 4.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.42	unconstrained · MANE · 9,714 bp · p 7.8e-09 · regional, not allelic
Overall
CADD	21.8	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 0.667% African / African-American · 501/75,058 alleles

Filtering AF 0.619% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.6%

Overall 0.0621% 1,002/1,614,006 alleles · rare exomes 709/1,461,680 · genomes 293/152,326 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.667%	150
Middle Eastern	0.116%	865
Remaining individualsnot grpmax-eligible	0.0624%	1,603
Admixed American	0.0433%	2,309
European (non-Finnish)	0.0363%	2,757
Finnishnot grpmax-eligible	0.00156%	64,004

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: MAP3K5
Protein: p.Ile708Val
Coding: c.2122A>G
MANE Select: NM_005923
Type: single nucleotide variant
Location: chr6:136622876 (GRCh38)
Gene constraint: LOEUF 0.433 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 73.87 · 27 PDB
Residue 708: the protein kinase domain; the 'interaction with ppia/cypa' region; a β-strand

Full MAP3K5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

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MAP3K5 p.Ala422Pro Uncertain significance ★ ⚠ same type
MAP3K5 p.Ala909Thr Uncertain significance ★ ⚠ same type
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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/map3k5-p-ile708val (accessed [today's date]).

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