Is THOC2 p.Ile635Phe (c.1903A>T) pathogenic?

THOC2 p.Ile635Phe (c.1903A>T) is classified Uncertain significance in THOC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-17). AlphaMissense: ambiguous (0.5259); Very rare (popmax 0.00175%, afr).

How common is THOC2 p.Ile635Phe (c.1903A>T) in the general population?

THOC2 p.Ile635Phe (c.1903A>T) is very rare (popmax 0.00175%, afr) (gnomAD).

What do computational predictors say about THOC2 p.Ile635Phe (c.1903A>T)?

AlphaMissense predicts ambiguous (score 0.5259) — an in-silico prediction, not a clinical call.

THOC2 p.Ile635Phe

c.1903A>T · VCV3391538

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5259 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00175%, afr)

Computational evidence

Protein change
AlphaMissense	0.5259	ambiguous
REVEL	0.373	indeterminate
SaProt	LLR -11.27	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.8, phastCons 1
Regional constraint	o/e 0.63	unconstrained · MANE · 49 kb · p 4.8e-11 · regional, not allelic
Overall
CADD	25.2	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 0.00175% African / African-American · 1/56,988 alleles

Filtering AF 3.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.4e-05%

Overall 0.00025% 3/1,197,661 alleles · very rare exomes 2/1,085,317 · genomes 1/112,344 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00175%	56,988
European (non-Finnish)	0.000226%	443,449

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.Ile635Phe
Coding: c.1903A>T
MANE Select: NM_001081550
Type: single nucleotide variant
Location: chrX:123638061 (GRCh38)
Structure: AlphaFold pLDDT 72.83 · 4 PDB
Residue 635: the 'mif4g domain; interaction with thoc3 and ddx39b' region

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-ile635phe (accessed [today's date]).

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