Is THOC2 p.Asp92Glu (c.276C>G) pathogenic?

THOC2 p.Asp92Glu (c.276C>G) is classified Uncertain significance in THOC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-08). AlphaMissense: likely pathogenic (0.9814); Very rare (popmax 0.000276%, nfe).

How common is THOC2 p.Asp92Glu (c.276C>G) in the general population?

THOC2 p.Asp92Glu (c.276C>G) is very rare (popmax 0.000276%, nfe) (gnomAD).

What do computational predictors say about THOC2 p.Asp92Glu (c.276C>G)?

AlphaMissense predicts likely pathogenic (score 0.9814) — an in-silico prediction, not a clinical call.

THOC2 p.Asp92Glu

c.276C>G · VCV4952671

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9814 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000276%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9814	likely pathogenic
REVEL	0.22	benign-leaning
SaProt	LLR -5.48	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.2, phastCons 1
Regional constraint	o/e 0.72	unconstrained · MANE · 35 kb · p 0.011 · regional, not allelic
Overall
CADD	22.4	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 0.000276% European (non-Finnish) · 2/725,057 alleles

Filtering AF 4.6e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.7e-05%

Overall 0.000301% 3/995,710 alleles · very rare exomes 3/882,078 · genomes 0/113,632 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00249%	40,171
European (non-Finnish)grpmax	0.000276%	362,529

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.Asp92Glu
Coding: c.276C>G
MANE Select: NM_001081550
Type: single nucleotide variant
Location: chrX:123697750 (GRCh38)
Structure: AlphaFold pLDDT 72.83 · 4 PDB
Residue 92: the 'anchor domain; interaction with thoc5 and thoc7' region; an α-helix

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-asp92glu (accessed [today's date]).

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