Is TGOLN2 p.Pro254Ala (c.760C>G) pathogenic?

TGOLN2 p.Pro254Ala (c.760C>G) is classified Uncertain significance in TGOLN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-17). AlphaMissense: likely benign (0.0616); Very rare (popmax 0.00667%, afr).

How common is TGOLN2 p.Pro254Ala (c.760C>G) in the general population?

TGOLN2 p.Pro254Ala (c.760C>G) is very rare (popmax 0.00667%, afr) (gnomAD).

What do computational predictors say about TGOLN2 p.Pro254Ala (c.760C>G)?

AlphaMissense predicts likely benign (score 0.0616) — an in-silico prediction, not a clinical call.

TGOLN2 p.Pro254Ala

c.760C>G · rs377141200 · VCV2402280

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0616 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0616	likely benign
REVEL	0.048	moderately benign-leaning
SaProt	LLR -4.80	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.34	GERP -2, phastCons 0.001
Regional constraint	o/e 0.97	unconstrained · MANE · 5,223 bp · p 0.42 · regional, not allelic
Overall
CADD	0.556	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 0.00667% African / African-American · 5/74,910 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00161%

Overall 0.000434% 7/1,613,816 alleles · very rare exomes 4/1,461,630 · genomes 3/152,186 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00667%	14,982
European (non-Finnish)	0.00017%	589,918

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.Pro254Ala
Coding: c.760C>G
MANE Select: NM_006464
dbSNP: rs377141200
Type: single nucleotide variant
Location: chr2:85326972 (GRCh38)
Gene constraint: LOEUF 0.913 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 49.67 · 1 PDB
Residue 254: the 'disordered' region

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

Similar variants

TGOLN2 p.Pro254Arg Uncertain significance ★ ⚠ same residue
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

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-pro254ala (accessed [today's date]).

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