Is THOC2 p.Asp472Ala (c.1415A>C) pathogenic?

THOC2 p.Asp472Ala (c.1415A>C) is classified Uncertain significance in THOC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-04-06). AlphaMissense: likely benign (0.1563); Very rare (popmax 0.000237%, nfe).

How common is THOC2 p.Asp472Ala (c.1415A>C) in the general population?

THOC2 p.Asp472Ala (c.1415A>C) is very rare (popmax 0.000237%, nfe) (gnomAD).

What do computational predictors say about THOC2 p.Asp472Ala (c.1415A>C)?

AlphaMissense predicts likely benign (score 0.1563) — an in-silico prediction, not a clinical call.

THOC2 p.Asp472Ala

c.1415A>C · VCV3764102

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1563 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000237%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1563	likely benign
REVEL	0.09	moderately benign-leaning
SaProt	LLR -7.73	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>C here scores Δ0.34 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.8	GERP 1.7, phastCons 1
Regional constraint	o/e 0.63	unconstrained · MANE · 49 kb · p 4.8e-11 · regional, not allelic
Overall
CADD	22.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

Grpmax group 0.000237% European (non-Finnish) · 2/843,276 alleles

Filtering AF 3.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.5e-05%

Overall 0.000176% 2/1,137,599 alleles · very rare exomes 2/1,023,852 · genomes 0/113,747 · 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.Asp472Ala
Coding: c.1415A>C
MANE Select: NM_001081550
Type: single nucleotide variant
Location: chrX:123645347 (GRCh38)
Structure: AlphaFold pLDDT 72.83 · 4 PDB
Residue 472: the 'bow domain; interaction with thoc1 dock domain and thoc3' region

Full THOC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

THOC2 p.Asp472_Lys473insAsp Uncertain significance ★ same residue
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

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-asp472ala (accessed [today's date]).

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