Is TSEN2 p.Arg397Ser (c.1191G>T) pathogenic?

TSEN2 p.Arg397Ser (c.1191G>T) is classified Uncertain significance in TSEN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-07). AlphaMissense: likely pathogenic (0.9342); Very rare (popmax 0.00534%, afr); Associated with Inborn genetic diseases.

What condition is associated with TSEN2 p.Arg397Ser (c.1191G>T)?

TSEN2 p.Arg397Ser (c.1191G>T) is associated with Inborn genetic diseases (ClinVar).

How common is TSEN2 p.Arg397Ser (c.1191G>T) in the general population?

TSEN2 p.Arg397Ser (c.1191G>T) is very rare (popmax 0.00534%, afr) (gnomAD).

What do computational predictors say about TSEN2 p.Arg397Ser (c.1191G>T)?

AlphaMissense predicts likely pathogenic (score 0.9342) — an in-silico prediction, not a clinical call.

TSEN2 p.Arg397Ser

c.1191G>T · VCV3462746

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9342 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00534%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9342	likely pathogenic · top 9% in TSEN2
REVEL	0.357	indeterminate
SaProt	LLR -7.84	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.41	GERP -4, phastCons 0.76
Regional constraint	o/e 1.10	unconstrained · MANE · 43 kb · p 0.013 · regional, not allelic
Overall
CADD	21.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00534% African / African-American · 4/74,892 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00031% 5/1,613,982 alleles · very rare exomes 4/1,461,874 · genomes 1/152,108 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00534%	18,723
Remaining individualsnot grpmax-eligible	0.0016%	62,488

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.Arg397Ser
Coding: c.1191G>T
MANE Select: NM_025265
Type: single nucleotide variant
Location: chr3:12529816 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TSEN2 p.Ala227Val Uncertain significance ★★ ⚠ same condition
TSEN2 p.Ala54Val Uncertain significance ★★ ⚠ same condition
TSEN2 p.Arg396His Uncertain significance ★★ ⚠ same condition
TSEN2 p.Asn282Ser Uncertain significance ★★ ⚠ same condition
TSEN2 p.Gly196Val Uncertain significance ★★ ⚠ same condition
TSEN2 p.His219Arg Uncertain significance ★★ ⚠ same condition
TSEN2 p.Ile25Val 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-arg397ser (accessed [today's date]).

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