Is THOC2 p.Ile689Val (c.2065A>G) pathogenic?

THOC2 p.Ile689Val (c.2065A>G) is classified Uncertain significance in THOC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-20). AlphaMissense: likely benign (0.2046); Absent from gnomAD v4.1.

How common is THOC2 p.Ile689Val (c.2065A>G) in the general population?

THOC2 p.Ile689Val (c.2065A>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about THOC2 p.Ile689Val (c.2065A>G)?

AlphaMissense predicts likely benign (score 0.2046) — an in-silico prediction, not a clinical call.

THOC2 p.Ile689Val

c.2065A>G · rs2521214896 · VCV2580065

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2046 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2046	likely benign
REVEL	0.473	indeterminate
SaProt	LLR -4.16	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.7, phastCons 1
Regional constraint	o/e 0.30	constrained · MANE · 13 kb · p 1.5e-33 · regional, not allelic
Overall
CADD	22.4	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: THOC2
Protein: p.Ile689Val
Coding: c.2065A>G
MANE Select: NM_001081550
dbSNP: rs2521214896
Type: single nucleotide variant
Location: chrX:123634024 (GRCh38)
Structure: AlphaFold pLDDT 72.83 · 4 PDB
Residue 689: the 'stern domain' region

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-ile689val (accessed [today's date]).

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