Is THOC2 p.Val111Ile (c.331G>A) pathogenic?

THOC2 p.Val111Ile (c.331G>A) is classified Uncertain significance in THOC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-15). AlphaMissense: likely benign (0.1609); Very rare (popmax 0.00979%, amr).

How common is THOC2 p.Val111Ile (c.331G>A) in the general population?

THOC2 p.Val111Ile (c.331G>A) is very rare (popmax 0.00979%, amr) (gnomAD).

What do computational predictors say about THOC2 p.Val111Ile (c.331G>A)?

AlphaMissense predicts likely benign (score 0.1609) — an in-silico prediction, not a clinical call.

THOC2 p.Val111Ile

c.331G>A · rs764037034 · VCV952567

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1609 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00979%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1609	likely benign
REVEL	0.116	moderately benign-leaning
SaProt	LLR -8.11	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.5, phastCons 1
Regional constraint	o/e 0.72	unconstrained · MANE · 35 kb · p 0.011 · regional, not allelic
Overall
CADD	22.6	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 0.00979% Admixed American · 4/40,848 alleles

Filtering AF 0.00328% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00194%

Overall 0.00156% 17/1,091,243 alleles · very rare exomes 11/979,225 · genomes 6/112,018 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00979%	10,212
Remaining individualsnot grpmax-eligible	0.00459%	21,796
African / African-American	0.00182%	54,875
European (non-Finnish)	0.00124%	80,504

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.Val111Ile
Coding: c.331G>A
MANE Select: NM_001081550
dbSNP: rs764037034
Type: single nucleotide variant
Location: chrX:123697695 (GRCh38)
Structure: AlphaFold pLDDT 72.83 · 4 PDB
Residue 111: 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-val111ile (accessed [today's date]).

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