Is THOC2 p.Met511Ile (c.1533G>A) pathogenic?

THOC2 p.Met511Ile (c.1533G>A) is classified Uncertain significance in THOC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-12). AlphaMissense: likely pathogenic (0.7955); Very rare (popmax 0.00304%, nfe).

How common is THOC2 p.Met511Ile (c.1533G>A) in the general population?

THOC2 p.Met511Ile (c.1533G>A) is very rare (popmax 0.00304%, nfe) (gnomAD).

What do computational predictors say about THOC2 p.Met511Ile (c.1533G>A)?

AlphaMissense predicts likely pathogenic (score 0.7955) — an in-silico prediction, not a clinical call.

THOC2 p.Met511Ile

c.1533G>A · VCV3731127

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7955 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00304%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7955	likely pathogenic
REVEL	0.092	moderately benign-leaning
SaProt	LLR -5.61	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 7.7	GERP 1.5, phastCons 1
Regional constraint	o/e 0.63	unconstrained · MANE · 49 kb · p 4.8e-11 · regional, not allelic
Overall
CADD	23.1	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 0.00304% European (non-Finnish) · 27/889,144 alleles

Filtering AF 0.00208% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00183%

Overall 0.00225% 27/1,201,185 alleles · very rare exomes 26/1,089,257 · genomes 1/111,928 · 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.Met511Ile
Coding: c.1533G>A
MANE Select: NM_001081550
Type: single nucleotide variant
Location: chrX:123644805 (GRCh38)
Structure: AlphaFold pLDDT 72.83 · 4 PDB
Residue 511: the 'bow domain; interaction with thoc1 dock domain and thoc3' 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-met511ile (accessed [today's date]).

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