Is TGOLN2 p.Pro81Ser (c.241C>T) pathogenic?

TGOLN2 p.Pro81Ser (c.241C>T) is classified Uncertain significance in TGOLN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-12). AlphaMissense: likely benign (0.0643); Very rare (popmax 0.0011%, sas).

How common is TGOLN2 p.Pro81Ser (c.241C>T) in the general population?

TGOLN2 p.Pro81Ser (c.241C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about TGOLN2 p.Pro81Ser (c.241C>T)?

AlphaMissense predicts likely benign (score 0.0643) — an in-silico prediction, not a clinical call.

TGOLN2 p.Pro81Ser

c.241C>T · rs779307628 · VCV2283306

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0643 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0643	likely benign
REVEL	0.04	moderately benign-leaning
SaProt	LLR -8.87	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -3.2	GERP -2.3
Regional constraint	o/e 0.97	unconstrained · MANE · 5,223 bp · p 0.42 · regional, not allelic
Overall
CADD	6.731	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 0.0011% South Asian · 1/91,072 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.00062% 10/1,613,762 alleles · very rare exomes 10/1,461,668 · genomes 0/152,094 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00156%	64,000
South Asiangrpmax	0.0011%	91,072
European (non-Finnish)	0.000678%	147,477

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: TGOLN2
Protein: p.Pro81Ser
Coding: c.241C>T
MANE Select: NM_006464
dbSNP: rs779307628
Type: single nucleotide variant
Location: chr2:85327491 (GRCh38)
Gene constraint: LOEUF 0.913 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 49.67 · 1 PDB
Residue 81: the 'disordered' region; the '14 x 14 aa tandem repeats' region

Full TGOLN2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TGOLN2 c.*42T>C Uncertain significance ★ same type
TGOLN2 c.*51C>G Uncertain significance ★ same type
TGOLN2 p.Ala13Val Uncertain significance ★ ⚠ same type
TGOLN2 p.Ala22Val Uncertain significance ★ ⚠ same type
TGOLN2 p.Ala393Gly Uncertain significance ★ ⚠ same type
TGOLN2 p.Ala397Val Uncertain significance ★ ⚠ same type
TGOLN2 p.Ala6Val Uncertain significance ★ ⚠ same type
TGOLN2 p.Arg259Pro 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/tgoln2-p-pro81ser (accessed [today's date]).

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