Is THOC2 p.Ser1209Phe (c.3626C>T) pathogenic?

THOC2 p.Ser1209Phe (c.3626C>T) is classified Uncertain significance in THOC2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-11). AlphaMissense: likely benign (0.0896); Very rare (popmax 0.000559%, nfe); Associated with Inborn genetic diseases.

What condition is associated with THOC2 p.Ser1209Phe (c.3626C>T)?

THOC2 p.Ser1209Phe (c.3626C>T) is associated with Inborn genetic diseases (ClinVar).

How common is THOC2 p.Ser1209Phe (c.3626C>T) in the general population?

THOC2 p.Ser1209Phe (c.3626C>T) is very rare (popmax 0.000559%, nfe) (gnomAD).

What do computational predictors say about THOC2 p.Ser1209Phe (c.3626C>T)?

AlphaMissense predicts likely benign (score 0.0896) — an in-silico prediction, not a clinical call.

THOC2 p.Ser1209Phe

c.3626C>T · rs1666536676 · VCV1314592

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0896 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000559%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0896	likely benign
REVEL	0.068	moderately benign-leaning
SaProt	LLR -10.47	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 2.9, phastCons 1
Regional constraint	o/e 0.64	unconstrained · MANE · 9,041 bp · p 1.8e-06 · regional, not allelic
Overall
CADD	22.9	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 0.000559% European (non-Finnish) · 5/895,036 alleles

Filtering AF 0.000164% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000119%

Overall 0.000496% 6/1,209,807 alleles · very rare exomes 5/1,097,626 · genomes 1/112,181 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0021%	47,579
European (non-Finnish)grpmax	0.000559%	179,007

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ser1209Phe
Coding: c.3626C>T
MANE Select: NM_001081550
dbSNP: rs1666536676
Type: single nucleotide variant
Location: chrX:123623161 (GRCh38)
Structure: AlphaFold pLDDT 72.83 · 4 PDB
Residue 1209: 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.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.Ser644Gly 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-ser1209phe (accessed [today's date]).

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