Is TSEN2 p.Glu321= (c.963G>A) pathogenic?

TSEN2 p.Glu321= (c.963G>A) is classified Benign in TSEN2 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-04). Common (popmax 5.54%, sas) — too common for a highly-penetrant pathogenic allele; Associated with pontocerebellar hypoplasia.

What condition is associated with TSEN2 p.Glu321= (c.963G>A)?

TSEN2 p.Glu321= (c.963G>A) is associated with pontocerebellar hypoplasia (ClinVar).

TSEN2 p.Glu321=

Q: How common is TSEN2 p.Glu321= (c.963G>A) in the general population?

TSEN2 p.Glu321= (c.963G>A) is common (popmax 5.54%, sas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.963G>A · rs17036879 · VCV137751

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Common

common (popmax 5.54%, sas) — too common for a highly-penetrant pathogenic allele

Conditions

pontocerebellar hypoplasia

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 1.5	GERP -3.5, phastCons 1
Overall
CADD	6.738	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 5.54% South Asian · 5,048/91,080 alleles

Filtering AF 5.41% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.36%

Overall 1.7% 27,438/1,614,074 alleles · common exomes 24,594/1,461,818 · genomes 2,844/152,256 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	5.54%	18
East Asian	4.26%	23
Admixed American	3.89%	26
Remaining individualsnot grpmax-eligible	1.88%	53
African / African-American	1.34%	75
European (non-Finnish)	1.28%	78
Middle Eastern	1.21%	83
Finnishnot grpmax-eligible	1.03%	97
Ashkenazi Jewishnot grpmax-eligible	0.334%	299

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: TSEN2
Protein: p.Glu321=
Coding: c.963G>A
MANE Select: NM_025265
dbSNP: rs17036879
Type: single nucleotide variant
Location: chr3:12519061 (GRCh38)
Gene constraint: LOEUF 1.212 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 73.63 · 5 PDB

Full TSEN2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

pontocerebellar hypoplasia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TSEN2 c.1099+1G>A Likely pathogenic ★★ same condition
TSEN2 p.Tyr19Ter Pathogenic/Likely pathogenic ★★ same condition
TSEN2 p.Ala227Val Uncertain significance ★★ ⚠ same condition
TSEN2 p.Asn282Ser Uncertain significance ★★ ⚠ same condition
TSEN2 p.Asp250Asn Uncertain significance ★★ ⚠ same condition
TSEN2 p.Glu212Ala Uncertain significance ★★ ⚠ same condition
TSEN2 p.Leu234Phe Uncertain significance ★★ ⚠ same condition
TSEN2 p.Phe40Cys Uncertain significance ★★ ⚠ 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/tsen2-p-glu321 (accessed [today's date]).

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