Is THOC2 p.Pro1446Ser (c.4336C>T) pathogenic?

THOC2 p.Pro1446Ser (c.4336C>T) is classified Uncertain significance in THOC2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-03-05). AlphaMissense: likely benign (0.0595); No allele count reported in gnomAD v4.1 (AN 1,194,410); Associated with Inborn genetic diseases.

What condition is associated with THOC2 p.Pro1446Ser (c.4336C>T)?

THOC2 p.Pro1446Ser (c.4336C>T) is associated with Inborn genetic diseases (ClinVar).

How common is THOC2 p.Pro1446Ser (c.4336C>T) in the general population?

THOC2 p.Pro1446Ser (c.4336C>T) is no allele count reported in gnomAD v4.1 (AN 1,194,410) (gnomAD).

What do computational predictors say about THOC2 p.Pro1446Ser (c.4336C>T)?

AlphaMissense predicts likely benign (score 0.0595) — an in-silico prediction, not a clinical call.

THOC2 p.Pro1446Ser

c.4336C>T · rs2147550641 · VCV1329531

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0595 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,194,410)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0595	likely benign
REVEL	0.068	moderately benign-leaning
SaProt	LLR -5.96	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.86 · evaluated, not missing
Constraint at this position
Conservation	phyloP 5.6	GERP 2.2, phastCons 1
Regional constraint	o/e 0.12	constrained · MANE · 77 bp · p 0.00023 · regional, not allelic
Overall
CADD	21.6	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

No allele count reported in gnomAD v4.1 (AN 1,194,410). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: THOC2
Protein: p.Pro1446Ser
Coding: c.4336C>T
MANE Select: NM_001081550
dbSNP: rs2147550641
Type: single nucleotide variant
Location: chrX:123614165 (GRCh38)
Structure: AlphaFold pLDDT 72.83 · 4 PDB
Residue 1446: the 'charged domain' region; the 'disordered' region

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.Pro1446= Benign/Likely benign ★★ 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.Ser1209Phe 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-pro1446ser (accessed [today's date]).

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