Is THOC2 p.Ser1555Phe (c.4664C>T) pathogenic?

THOC2 p.Ser1555Phe (c.4664C>T) is classified Uncertain significance in THOC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-17). AlphaMissense: likely benign (0.2004); Very rare (popmax 0.000336%, nfe).

How common is THOC2 p.Ser1555Phe (c.4664C>T) in the general population?

THOC2 p.Ser1555Phe (c.4664C>T) is very rare (popmax 0.000336%, nfe) (gnomAD).

What do computational predictors say about THOC2 p.Ser1555Phe (c.4664C>T)?

AlphaMissense predicts likely benign (score 0.2004) — an in-silico prediction, not a clinical call.

THOC2 p.Ser1555Phe

c.4664C>T · rs1474472931 · VCV2429653

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2004 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000336%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.2004	likely benign
REVEL	0.424	indeterminate
SaProt	LLR -10.19	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 2.8, phastCons 1
Regional constraint	o/e 0.42	unconstrained · MANE · 3,154 bp · p 2.1e-08 · regional, not allelic
Overall
CADD	24.3	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 0.000336% European (non-Finnish) · 3/892,245 alleles

Filtering AF 9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.5e-05%

Overall 0.000249% 3/1,203,611 alleles · very rare exomes 1/1,092,641 · genomes 2/110,970 · 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.Ser1555Phe
Coding: c.4664C>T
MANE Select: NM_001081550
dbSNP: rs1474472931
Type: single nucleotide variant
Location: chrX:123613412 (GRCh38)
Structure: AlphaFold pLDDT 72.83 · 4 PDB
Residue 1555: the 'charged domain' region; the 'disordered' 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-ser1555phe (accessed [today's date]).

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