Is JUN p.Gln218Arg (c.653A>G) pathogenic?

JUN p.Gln218Arg (c.653A>G) is classified Uncertain significance in JUN (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-30). AlphaMissense: ambiguous (0.4142); Ultra-rare (popmax 0.0737%, sas).

How common is JUN p.Gln218Arg (c.653A>G) in the general population?

JUN p.Gln218Arg (c.653A>G) is ultra-rare (popmax 0.0737%, sas) (gnomAD).

What do computational predictors say about JUN p.Gln218Arg (c.653A>G)?

AlphaMissense predicts ambiguous (score 0.4142) — an in-silico prediction, not a clinical call.

JUN p.Gln218Arg

c.653A>G · VCV3287273

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4142 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0737%, sas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.4142	ambiguous
REVEL	0.107	moderately benign-leaning
SaProt	LLR -9.13	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.3	GERP -0.4, phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 313 bp · p 0.14 · regional, not allelic
Overall
CADD	21.6	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 0.0737% South Asian · 67/90,878 alleles

Filtering AF 0.0595% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0543%

Overall 0.0046% 74/1,608,848 alleles · ultra-rare exomes 70/1,456,492 · genomes 4/152,356 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0737%	1,356
Remaining individualsnot grpmax-eligible	0.00482%	20,743
African / African-American	0.00134%	74,828
European (non-Finnish)	0.000255%	392,528

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: JUN
Protein: p.Gln218Arg
Coding: c.653A>G
MANE Select: NM_002228
Type: single nucleotide variant
Location: chr1:58782418 (GRCh38)
Gene constraint: LOEUF 0.716 · pLI 0.47 (gnomAD)
Structure: AlphaFold pLDDT 62.45 · 10 PDB
Residue 218: the 'interaction with page4' region

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

Similar variants

JUN p.Ala148Val Uncertain significance ★ ⚠ same type
JUN p.Ala161Ser Uncertain significance ★ ⚠ same type
JUN p.Ala187Ser Uncertain significance ★ ⚠ same type
JUN p.Ala224Gly Uncertain significance ★ ⚠ same type
JUN p.Asn175Asp Uncertain significance ★ ⚠ same type
JUN p.Asn314Lys Uncertain significance ★ ⚠ same type
JUN p.Gln290Arg Uncertain significance ★ ⚠ same type
JUN p.Gln290Glu 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/jun-p-gln218arg (accessed [today's date]).

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