Is MAP2K7 p.Arg217Cys (c.649C>T) pathogenic?

MAP2K7 p.Arg217Cys (c.649C>T) is classified Uncertain significance in MAP2K7 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-24). AlphaMissense: likely benign (0.1628); Ultra-rare (popmax 0.0164%, mid).

How common is MAP2K7 p.Arg217Cys (c.649C>T) in the general population?

MAP2K7 p.Arg217Cys (c.649C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about MAP2K7 p.Arg217Cys (c.649C>T)?

AlphaMissense predicts likely benign (score 0.1628) — an in-silico prediction, not a clinical call.

MAP2K7 p.Arg217Cys

c.649C>T · rs745624779 · VCV2550876

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1628 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1628	likely benign
REVEL	0.26	benign-leaning
SaProt	LLR -12.11	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.6	GERP 0.32, phastCons 1
Regional constraint	o/e 0.56	unconstrained · MANE · 1,458 bp · p 2.3e-17 · regional, not allelic
Overall
CADD	23.9	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0164% Middle Eastern · 1/6,082 alleles

Filtering AF 0.00375% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00337%

Overall 0.00385% 62/1,611,428 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,082
European (non-Finnish)	0.00475%	21,059
South Asian	0.0044%	22,716
East Asian	0.00223%	44,784

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: MAP2K7
Protein: p.Arg217Cys
Coding: c.649C>T
MANE Select: NM_145185
dbSNP: rs745624779
Type: single nucleotide variant
Location: chr19:7910777 (GRCh38)
Gene constraint: LOEUF 0.454 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 77.94 · 37 PDB
Residue 217: the protein kinase domain; an α-helix

Full MAP2K7 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MAP2K7 p.Arg217His Uncertain significance ★ ⚠ same residue
MAP2K7 c.855+10G>C Benign ★★ same type
MAP2K7 c.856-19T>C Benign ★★ same type
MAP2K7 c.856-8C>G Benign ★★ same type
MAP2K7 p.Cys131= Benign ★★ same type
MAP2K7 p.Pro215= Benign ★★ same type
MAP2K7 p.Ser277= Benign ★★ same type
MAP2K7 p.Ala391Val 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/map2k7-p-arg217cys (accessed [today's date]).

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