Is THOC2 p.Arg77Cys (c.229C>T) pathogenic?

THOC2 p.Arg77Cys (c.229C>T) is classified Conflicting classifications of pathogenicity in THOC2 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-02-11). AlphaMissense: ambiguous (0.3764); No allele count reported in gnomAD v4.1 (AN 1,156,398); Associated with Inborn genetic diseases.

What condition is associated with THOC2 p.Arg77Cys (c.229C>T)?

THOC2 p.Arg77Cys (c.229C>T) is associated with Inborn genetic diseases, X-linked intellectual disability-short stature-overweight syndrome (ClinVar).

How common is THOC2 p.Arg77Cys (c.229C>T) in the general population?

THOC2 p.Arg77Cys (c.229C>T) is no allele count reported in gnomAD v4.1 (AN 1,156,398) (gnomAD).

What do computational predictors say about THOC2 p.Arg77Cys (c.229C>T)?

AlphaMissense predicts ambiguous (score 0.3764) — an in-silico prediction, not a clinical call.

THOC2 p.Arg77Cys

c.229C>T · rs1556302160 · VCV488436

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

ambiguous

0.3764 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,156,398)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3764	ambiguous
REVEL	0.271	benign-leaning
SaProt	LLR -7.30	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	Δ0.27	acceptor loss · deltas
Pangolin	Δ0.30	loss · gain 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.4	GERP 2.3, phastCons 1
Regional constraint	o/e 0.72	unconstrained · MANE · 35 kb · p 0.011 · regional, not allelic
Overall
CADD	23.7	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

No allele count reported in gnomAD v4.1 (AN 1,156,398). 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.Arg77Cys
Coding: c.229C>T
MANE Select: NM_001081550
dbSNP: rs1556302160
Type: single nucleotide variant
Location: chrX:123703499 (GRCh38)
Structure: AlphaFold pLDDT 72.83 · 4 PDB
Residue 77: the 'anchor domain; interaction with thoc5 and thoc7' region; a UniProt-annotated variant site (in mrxsk; likely pathogenic; decreased protein abundance); 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

Also linked: X-linked intellectual disability-short stature-overweight syndrome

Similar variants

THOC2 p.Cys615Tyr Likely pathogenic ★★ same condition
THOC2 p.Thr696Ile Pathogenic/Likely pathogenic ★★ same condition
THOC2 p.Ala912Pro Uncertain significance ★★ ⚠ same condition
THOC2 p.Arg1307Trp Uncertain significance ★★ ⚠ same condition
THOC2 p.Asn208Ser Uncertain significance ★★ ⚠ same condition
THOC2 p.Asn414Tyr Uncertain significance ★★ ⚠ same condition
THOC2 p.Asp656Gly Uncertain significance ★★ ⚠ same condition
THOC2 p.Gly1205Arg 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-arg77cys (accessed [today's date]).

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