Is TSEN2 p.Pro135= (c.405G>A) pathogenic?

TSEN2 p.Pro135= (c.405G>A) is classified Benign/Likely benign in TSEN2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-13). Rare (popmax 0.32%, afr); Associated with pontocerebellar hypoplasia.

What condition is associated with TSEN2 p.Pro135= (c.405G>A)?

TSEN2 p.Pro135= (c.405G>A) is associated with pontocerebellar hypoplasia (ClinVar).

How common is TSEN2 p.Pro135= (c.405G>A) in the general population?

TSEN2 p.Pro135= (c.405G>A) is rare (popmax 0.32%, afr) (gnomAD).

TSEN2 p.Pro135=

c.405G>A · rs140728375 · VCV736209

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

rare (popmax 0.32%, afr)

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 -2.8	GERP -3.6
Overall
CADD	0.611	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.32% African / African-American · 240/75,050 alleles

Filtering AF 0.287% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.274%

Overall 0.024% 387/1,614,202 alleles · rare exomes 264/1,461,886 · genomes 123/152,316 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.32%	313
Remaining individualsnot grpmax-eligible	0.0224%	4,465
Admixed American	0.0167%	6,002
South Asian	0.00988%	10,120
European (non-Finnish)	0.00941%	10,631
East Asian	0.00668%	14,963

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.Pro135=
Coding: c.405G>A
MANE Select: NM_025265
dbSNP: rs140728375
Type: single nucleotide variant
Location: chr3:12503358 (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 p.Pro135Leu Uncertain significance ★★ ⚠ same residue
TSEN2 p.Pro135Ser Uncertain significance ★ ⚠ same residue
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

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-pro135 (accessed [today's date]).

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