Is JAG1 p.Pro331= (c.993C>T) pathogenic?

JAG1 p.Pro331= (c.993C>T) is classified Likely benign in JAG1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-11-01). Very rare (popmax 0.00267%, afr); Associated with deafness, congenital heart defects, and posterior embryotoxon.

What condition is associated with JAG1 p.Pro331= (c.993C>T)?

JAG1 p.Pro331= (c.993C>T) is associated with deafness, congenital heart defects, and posterior embryotoxon, tetralogy of fallot, Alagille syndrome due to a JAG1 point mutation (ClinVar).

How common is JAG1 p.Pro331= (c.993C>T) in the general population?

JAG1 p.Pro331= (c.993C>T) is very rare (popmax 0.00267%, afr) (gnomAD).

JAG1 p.Pro331=

c.993C>T · rs1294629128 · VCV1088960

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Conditions

deafness, congenital heart defects, and posterior embryotoxon

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.5	GERP -0.074, phastCons 1
Overall
CADD	10.85	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00267% African / African-American · 2/74,850 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000248% 4/1,613,752 alleles · very rare exomes 2/1,461,682 · genomes 2/152,070 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,425
European (non-Finnish)	0.00017%	589,932

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: JAG1
Protein: p.Pro331=
Coding: c.993C>T
MANE Select: NM_000214
dbSNP: rs1294629128
Type: single nucleotide variant
Location: chr20:10652144 (GRCh38)
Gene constraint: LOEUF 0.211 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 73.02 · 7 PDB
Residue 331: the egf-like 3 domain

Full JAG1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

deafness, congenital heart defects, and posterior embryotoxon — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: tetralogy of fallot Alagille syndrome due to a JAG1 point mutation Charcot-Marie-Tooth disease, axonal, Type 2HH

Similar variants

JAG1 p.Pro331His Uncertain significance ★ ⚠ same residue
JAG1 c.1395+3A>G Pathogenic ★★ same condition
JAG1 c.2113+1G>A Likely pathogenic ★★ same condition
JAG1 c.2113+1G>T Pathogenic/Likely pathogenic ★★ same condition
JAG1 c.2572+1G>T Pathogenic/Likely pathogenic ★★ same condition
JAG1 c.439+1G>A Pathogenic ★★ same condition
JAG1 c.886+1G>A Pathogenic ★★ same condition
JAG1 p.Arg184Cys Pathogenic/Likely pathogenic ★★ same condition

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/jag1-p-pro331 (accessed [today's date]).

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