Is JUNB p.Pro221Ser (c.661C>T) pathogenic?

JUNB p.Pro221Ser (c.661C>T) is classified Uncertain significance in JUNB (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-10). AlphaMissense: likely benign (0.0628); Ultra-rare (popmax 0.016%, afr).

How common is JUNB p.Pro221Ser (c.661C>T) in the general population?

JUNB p.Pro221Ser (c.661C>T) is ultra-rare (popmax 0.016%, afr) (gnomAD).

What do computational predictors say about JUNB p.Pro221Ser (c.661C>T)?

AlphaMissense predicts likely benign (score 0.0628) — an in-silico prediction, not a clinical call.

JUNB p.Pro221Ser

c.661C>T · VCV3287276

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0628 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.016%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0628	likely benign
REVEL	0.206	benign-leaning
SaProt	LLR -6.41	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 7.6	GERP 0.39, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 816 bp · p 0.039 · regional, not allelic
Overall
CADD	23.8	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 0.016% African / African-American · 12/74,850 alleles

Filtering AF 0.00922% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00722%

Overall 0.000936% 15/1,601,992 alleles · ultra-rare exomes 9/1,449,782 · genomes 6/152,210 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.016%	6,237
South Asian	0.00221%	45,237
European (non-Finnish)	8.49e-05%	1,177,468

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: JUNB
Protein: p.Pro221Ser
Coding: c.661C>T
MANE Select: NM_002229
Type: single nucleotide variant
Location: chr19:12792432 (GRCh38)
Gene constraint: LOEUF 0.86 · pLI 0.23 (gnomAD)
Structure: AlphaFold pLDDT 61.35

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

Similar variants

JUNB p.Ala236Thr Uncertain significance ★ ⚠ same type
JUNB p.Ala249Val Uncertain significance ★ ⚠ same type
JUNB p.Arg250His Uncertain significance ★ ⚠ same type
JUNB p.Glu267Gly Uncertain significance ★ ⚠ same type
JUNB p.His218Arg Uncertain significance ★ ⚠ same type
JUNB p.Ile261Val Uncertain significance ★ ⚠ same type
JUNB p.Leu230Pro Uncertain significance ★ ⚠ same type
JUNB p.Met329Leu 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/junb-p-pro221ser (accessed [today's date]).

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