Is MAPK7 p.Arg538Gln (c.1613G>A) pathogenic?

MAPK7 p.Arg538Gln (c.1613G>A) is classified Uncertain significance in MAPK7 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-07). AlphaMissense: likely benign (0.1005); Very rare (popmax 0.00592%, sas).

How common is MAPK7 p.Arg538Gln (c.1613G>A) in the general population?

MAPK7 p.Arg538Gln (c.1613G>A) is very rare (popmax 0.00592%, sas) (gnomAD).

What do computational predictors say about MAPK7 p.Arg538Gln (c.1613G>A)?

AlphaMissense predicts likely benign (score 0.1005) — an in-silico prediction, not a clinical call.

MAPK7 p.Arg538Gln

c.1613G>A · VCV3293239

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1005 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00592%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1005	likely benign
REVEL	0.37	indeterminate
SaProt	LLR -8.90	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.7	phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 1,234 bp · p 6.6e-06 · regional, not allelic
Overall
CADD	25.4	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 0.00592% South Asian · 5/84,454 alleles

Filtering AF 0.00233% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00146%

Overall 0.00167% 26/1,554,138 alleles · very rare exomes 24/1,401,856 · genomes 2/152,282 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00592%	16,891
Admixed American	0.00391%	25,548
Remaining individualsnot grpmax-eligible	0.00166%	60,252
European (non-Finnish)	0.00157%	63,801

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: MAPK7
Protein: p.Arg538Gln
Coding: c.1613G>A
MANE Select: NM_002749
Type: single nucleotide variant
Location: chr17:19381916 (GRCh38)
Gene constraint: LOEUF 0.689 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 66.87 · 14 PDB
Residue 538: the 'disordered' region; the 'may not be required for kinase activity; required to stimulate mef2c activity' region

Full MAPK7 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MAPK7 p.Pro551Ser Benign/Likely benign ★★ same type
MAPK7 p.Ala288Ser Uncertain significance ★ ⚠ same type
MAPK7 p.Ala29Gly Uncertain significance ★ ⚠ same type
MAPK7 p.Ala334Thr Uncertain significance ★ ⚠ same type
MAPK7 p.Ala348Ser Uncertain significance ★ ⚠ same type
MAPK7 p.Ala360Val Uncertain significance ★ ⚠ same type
MAPK7 p.Ala481Ser Uncertain significance ★ ⚠ same type
MAPK7 p.Ala497Val 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/mapk7-p-arg538gln (accessed [today's date]).

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