Is JUN p.Leu14Phe (c.40C>T) pathogenic?

JUN p.Leu14Phe (c.40C>T) is classified Uncertain significance in JUN (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-17). AlphaMissense: likely benign (0.1406); Very rare (popmax 0.005%, amr).

How common is JUN p.Leu14Phe (c.40C>T) in the general population?

JUN p.Leu14Phe (c.40C>T) is very rare (popmax 0.005%, amr) (gnomAD).

What do computational predictors say about JUN p.Leu14Phe (c.40C>T)?

AlphaMissense predicts likely benign (score 0.1406) — an in-silico prediction, not a clinical call.

JUN p.Leu14Phe

c.40C>T · rs542953484 · VCV2361623

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1406 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1406	likely benign
REVEL	0.087	moderately benign-leaning
SaProt	LLR -5.58	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.6	GERP 1.1, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 311 bp · p 0.041 · regional, not allelic
Overall
CADD	21.3	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 0.005% Admixed American · 3/60,030 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.00062% 10/1,614,198 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	20,010
Remaining individualsnot grpmax-eligible	0.0032%	31,254
Finnishnot grpmax-eligible	0.00312%	32,019
East Asian	0.00223%	44,884
European (non-Finnish)	0.000169%	590,012

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.Leu14Phe
Coding: c.40C>T
MANE Select: NM_002228
dbSNP: rs542953484
Type: single nucleotide variant
Location: chr1:58783031 (GRCh38)
Gene constraint: LOEUF 0.716 · pLI 0.47 (gnomAD)
Structure: AlphaFold pLDDT 62.45 · 10 PDB

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.Gln218Arg Uncertain significance ★ ⚠ same type
JUN p.Gln290Arg 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-leu14phe (accessed [today's date]).

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