Is THOC2 p.Ser726Phe (c.2177C>T) pathogenic?

THOC2 p.Ser726Phe (c.2177C>T) is classified Uncertain significance in THOC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-11). AlphaMissense: likely pathogenic (0.9964); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with THOC2 p.Ser726Phe (c.2177C>T)?

THOC2 p.Ser726Phe (c.2177C>T) is associated with Inborn genetic diseases (ClinVar).

How common is THOC2 p.Ser726Phe (c.2177C>T) in the general population?

THOC2 p.Ser726Phe (c.2177C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about THOC2 p.Ser726Phe (c.2177C>T)?

AlphaMissense predicts likely pathogenic (score 0.9964) — an in-silico prediction, not a clinical call.

THOC2 p.Ser726Phe

c.2177C>T · rs2521191305 · VCV3177082

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9964 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9964	likely pathogenic · top 7% in THOC2
REVEL	0.796	moderately pathogenic-leaning
SaProt	LLR -11.88	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 2.6, phastCons 1
Regional constraint	o/e 0.30	constrained · MANE · 13 kb · p 1.5e-33 · regional, not allelic
Overall
CADD	28.5	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

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.Ser726Phe
Coding: c.2177C>T
MANE Select: NM_001081550
dbSNP: rs2521191305
Type: single nucleotide variant
Location: chrX:123633000 (GRCh38)
Structure: AlphaFold pLDDT 72.83 · 4 PDB
Residue 726: the 'stern domain' 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.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
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-ser726phe (accessed [today's date]).

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