Is THOC2 p.Arg522His (c.1565G>A) pathogenic?

THOC2 p.Arg522His (c.1565G>A) is classified Uncertain significance in THOC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-05). AlphaMissense: ambiguous (0.5413); Very rare (popmax 0.00298%, eas); Associated with Inborn genetic diseases.

What condition is associated with THOC2 p.Arg522His (c.1565G>A)?

THOC2 p.Arg522His (c.1565G>A) is associated with Inborn genetic diseases (ClinVar).

How common is THOC2 p.Arg522His (c.1565G>A) in the general population?

THOC2 p.Arg522His (c.1565G>A) is very rare (popmax 0.00298%, eas) (gnomAD).

What do computational predictors say about THOC2 p.Arg522His (c.1565G>A)?

AlphaMissense predicts ambiguous (score 0.5413) — an in-silico prediction, not a clinical call.

THOC2 p.Arg522His

c.1565G>A · rs2521396749 · VCV2270183

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5413 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00298%, eas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5413	ambiguous
REVEL	0.265	benign-leaning
SaProt	LLR -8.59	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.3	GERP 0.67, phastCons 1
Regional constraint	o/e 0.63	unconstrained · MANE · 49 kb · p 4.8e-11 · regional, not allelic
Overall
CADD	22.4	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 0.00298% East Asian · 1/33,583 alleles

Filtering AF 0.00102% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000806%

Overall 0.00134% 16/1,192,993 alleles · very rare exomes 15/1,081,373 · genomes 1/111,620 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00298%	33,583
European (non-Finnish)	0.00169%	59,071

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: THOC2
Protein: p.Arg522His
Coding: c.1565G>A
MANE Select: NM_001081550
dbSNP: rs2521396749
Type: single nucleotide variant
Location: chrX:123644671 (GRCh38)
Structure: AlphaFold pLDDT 72.83 · 4 PDB
Residue 522: the 'bow domain; interaction with thoc1 dock domain and thoc3' region; an α-helix

Full THOC2 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

THOC2 p.Arg522Cys Uncertain significance ★ ⚠ same residue
THOC2 p.Arg1307Trp Uncertain significance ★★ ⚠ same condition
THOC2 p.Asn414Tyr Uncertain significance ★★ ⚠ same condition
THOC2 p.Gly1205Arg Uncertain significance ★★ same condition
THOC2 p.Lys1302Arg Uncertain significance ★★ ⚠ same condition
THOC2 p.Lys957Arg Uncertain significance ★★ ⚠ same condition
THOC2 p.Met1373Thr Uncertain significance ★★ ⚠ same condition
THOC2 p.Pro1446Ser 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/thoc2-p-arg522his (accessed [today's date]).

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