Is MAP3K7 p.Arg56Ser (c.168A>C) pathogenic?

MAP3K7 p.Arg56Ser (c.168A>C) is classified Uncertain significance in MAP3K7 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-18). AlphaMissense: likely pathogenic (0.961); Very rare (popmax 0.00339%, amr).

How common is MAP3K7 p.Arg56Ser (c.168A>C) in the general population?

MAP3K7 p.Arg56Ser (c.168A>C) is very rare (popmax 0.00339%, amr) (gnomAD).

What do computational predictors say about MAP3K7 p.Arg56Ser (c.168A>C)?

AlphaMissense predicts likely pathogenic (score 0.961) — an in-silico prediction, not a clinical call.

MAP3K7 p.Arg56Ser

c.168A>C · VCV3628936

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.961 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00339%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.961	likely pathogenic
REVEL	0.406	indeterminate
SaProt	LLR -11.91	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 6.2	GERP 1.6, phastCons 1
Regional constraint	o/e 0.36	constrained · MANE · 35 kb · p 4.4e-26 · regional, not allelic
Overall
CADD	26.7	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 0.00339% Admixed American · 2/58,936 alleles

Filtering AF 0.000563% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000187% 3/1,607,040 alleles · very rare exomes 3/1,454,942 · genomes 0/152,098 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00339%	29,468
European (non-Finnish)	8.5e-05%	1,177,042

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: MAP3K7
Protein: p.Arg56Ser
Coding: c.168A>C
MANE Select: NM_145331
Type: single nucleotide variant
Location: chr6:90571760 (GRCh38)
Gene constraint: LOEUF 0.397 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 70.27 · 25 PDB
Residue 56: the protein kinase domain; the 'interaction with mapk8ip1' region; a β-strand

Full MAP3K7 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MAP3K7 p.Arg56= Likely benign ★ same residue
MAP3K7 p.Arg274Cys Pathogenic/Likely pathogenic ★★ same type
MAP3K7 p.Gly110Ser Pathogenic/Likely pathogenic ★★ same type
MAP3K7 p.Pro512Leu Pathogenic ★★ same type
MAP3K7 p.Ala313Thr Uncertain significance ★★ ⚠ same type
MAP3K7 p.Ala400Thr Uncertain significance ★★ ⚠ same type
MAP3K7 p.Ala6Thr Uncertain significance ★★ ⚠ same type
MAP3K7 p.Arg289Gln 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/map3k7-p-arg56ser (accessed [today's date]).

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