Is TGOLN2 p.Arg407Gln (c.1220G>A) pathogenic?

TGOLN2 p.Arg407Gln (c.1220G>A) is classified Uncertain significance in TGOLN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-12). AlphaMissense: ambiguous (0.4781); Very rare (popmax 0.00085%, nfe).

How common is TGOLN2 p.Arg407Gln (c.1220G>A) in the general population?

TGOLN2 p.Arg407Gln (c.1220G>A) is very rare (popmax 0.00085%, nfe) (gnomAD).

What do computational predictors say about TGOLN2 p.Arg407Gln (c.1220G>A)?

AlphaMissense predicts ambiguous (score 0.4781) — an in-silico prediction, not a clinical call.

TGOLN2 p.Arg407Gln

c.1220G>A · rs754061348 · VCV3176783

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4781 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00085%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4781	ambiguous
REVEL	0.272	benign-leaning
SaProt	LLR -11.74	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.3	GERP 1.3, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 5,223 bp · p 0.42 · regional, not allelic
Overall
CADD	28.5	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 0.00085% European (non-Finnish) · 10/1,176,596 alleles

Filtering AF 0.00043% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000313%

Overall 0.000621% 10/1,609,798 alleles · very rare exomes 9/1,457,638 · genomes 1/152,160 · joint denominator

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.Arg407Gln
Coding: c.1220G>A
MANE Select: NM_006464
dbSNP: rs754061348
Type: single nucleotide variant
Location: chr2:85326512 (GRCh38)
Gene constraint: LOEUF 0.913 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 49.67 · 1 PDB

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-arg407gln (accessed [today's date]).

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