Is THOC2 p.Val337Ala (c.1010T>C) pathogenic?

THOC2 p.Val337Ala (c.1010T>C) is classified Uncertain significance in THOC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-01). AlphaMissense: likely benign (0.0775); Very rare (popmax 0.00579%, sas); Associated with X-linked intellectual disability-short stature-overweight syndrome.

What condition is associated with THOC2 p.Val337Ala (c.1010T>C)?

THOC2 p.Val337Ala (c.1010T>C) is associated with X-linked intellectual disability-short stature-overweight syndrome (ClinVar).

How common is THOC2 p.Val337Ala (c.1010T>C) in the general population?

THOC2 p.Val337Ala (c.1010T>C) is very rare (popmax 0.00579%, sas) (gnomAD).

What do computational predictors say about THOC2 p.Val337Ala (c.1010T>C)?

AlphaMissense predicts likely benign (score 0.0775) — an in-silico prediction, not a clinical call.

THOC2 p.Val337Ala

c.1010T>C · rs2521725154 · VCV2664798

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0775 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00579%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

X-linked intellectual disability-short stature-overweight syndrome

Computational evidence

Protein change
AlphaMissense	0.0775	likely benign
REVEL	0.061	moderately benign-leaning
SaProt	LLR -6.91	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 7.9	GERP 5.5, phastCons 1
Regional constraint	o/e 0.63	unconstrained · MANE · 49 kb · p 4.8e-11 · regional, not allelic
Overall
CADD	18.73	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 0.00579% South Asian · 3/51,820 alleles

Filtering AF 0.00154% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000826%

Overall 0.000255% 3/1,178,307 alleles · very rare exomes 3/1,064,403 · genomes 0/113,904 · 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.Val337Ala
Coding: c.1010T>C
MANE Select: NM_001081550
dbSNP: rs2521725154
Type: single nucleotide variant
Location: chrX:123668166 (GRCh38)
Structure: AlphaFold pLDDT 72.83 · 4 PDB
Residue 337: the 'bow domain; interaction with thoc1 dock domain and thoc3' region; the 'disordered' region

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

Disease context

X-linked intellectual disability-short stature-overweight syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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.Asn208Ser Uncertain significance ★★ ⚠ same condition
THOC2 p.Asp656Gly Uncertain significance ★★ ⚠ same condition
THOC2 p.Gly1205Arg Uncertain significance ★★ same condition
THOC2 p.Pro1416Ser Uncertain significance ★★ ⚠ same condition
THOC2 c.2317-47A>G Benign ★★ 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-val337ala (accessed [today's date]).

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