Is THOC2 p.Pro290Leu (c.869C>T) pathogenic?

THOC2 p.Pro290Leu (c.869C>T) is classified Uncertain significance in THOC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-03). AlphaMissense: likely pathogenic (0.9686); Very rare (popmax 0.00115%, nfe).

How common is THOC2 p.Pro290Leu (c.869C>T) in the general population?

THOC2 p.Pro290Leu (c.869C>T) is very rare (popmax 0.00115%, nfe) (gnomAD).

What do computational predictors say about THOC2 p.Pro290Leu (c.869C>T)?

AlphaMissense predicts likely pathogenic (score 0.9686) — an in-silico prediction, not a clinical call.

THOC2 p.Pro290Leu

c.869C>T · rs2521727268 · VCV2579455

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9686 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00115%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9686	likely pathogenic
REVEL	0.718	pathogenic-leaning
SaProt	LLR -13.77	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.38 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	GERP 5.5, phastCons 1
Regional constraint	o/e 0.63	unconstrained · MANE · 49 kb · p 4.8e-11 · regional, not allelic
Overall
CADD	26.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00115% European (non-Finnish) · 10/873,046 alleles

Filtering AF 0.000579% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000422%

Overall 0.000857% 10/1,166,516 alleles · very rare exomes 10/1,053,264 · genomes 0/113,252 · 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: THOC2
Protein: p.Pro290Leu
Coding: c.869C>T
MANE Select: NM_001081550
dbSNP: rs2521727268
Type: single nucleotide variant
Location: chrX:123668307 (GRCh38)
Structure: AlphaFold pLDDT 72.83 · 4 PDB
Residue 290: the 'bow domain; interaction with thoc1 dock domain and thoc3' region; a β-strand

Full THOC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

THOC2 p.Cys615Tyr Likely pathogenic ★★ same type
THOC2 p.Thr696Ile Pathogenic/Likely pathogenic ★★ same type
THOC2 p.Ala912Pro Uncertain significance ★★ ⚠ same type
THOC2 p.Arg1307Trp Uncertain significance ★★ ⚠ same type
THOC2 p.Arg1468Lys Uncertain significance ★★ ⚠ same type
THOC2 p.Asn208Ser Uncertain significance ★★ ⚠ same type
THOC2 p.Asn414Tyr Uncertain significance ★★ ⚠ same type
THOC2 p.Asn666Ser 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/thoc2-p-pro290leu (accessed [today's date]).

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