Is TMX2 p.Phe36Ser (c.107T>C) pathogenic?

TMX2 p.Phe36Ser (c.107T>C) is classified Uncertain significance in TMX2 (ClinVar, Single submitter, 1 submitter). AlphaMissense: likely pathogenic (0.9807); Very rare (popmax 0.0011%, sas); Associated with neurodevelopmental disorder with microcephaly, cortical malformations, and spasticity.

How common is TMX2 p.Phe36Ser (c.107T>C) in the general population?

TMX2 p.Phe36Ser (c.107T>C) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about TMX2 p.Phe36Ser (c.107T>C)?

AlphaMissense predicts likely pathogenic (score 0.9807) — an in-silico prediction, not a clinical call.

TMX2 p.Phe36Ser

Q: What condition is associated with TMX2 p.Phe36Ser (c.107T>C)?

TMX2 p.Phe36Ser (c.107T>C) is associated with neurodevelopmental disorder with microcephaly, cortical malformations, and spasticity (ClinVar).

c.107T>C · rs2495047614 · VCV2585461

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9807 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neurodevelopmental disorder with microcephaly, cortical malformations, and spasticity

Computational evidence

Protein change
AlphaMissense	0.9807	likely pathogenic · top 10% in TMX2
REVEL	0.706	pathogenic-leaning
SaProt	LLR -10.06	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2, phastCons 1
Regional constraint	o/e 1.28	unconstrained · MANE · 25 kb · p 0.01 · regional, not allelic
Overall
CADD	27.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0011% South Asian · 1/91,084 alleles

Overall 6.2e-05% 1/1,614,178 alleles · very rare exomes 1/1,461,836 · genomes 0/152,342 · 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: TMX2
Protein: p.Phe36Ser
Coding: c.107T>C
MANE Select: NM_015959
dbSNP: rs2495047614
Type: single nucleotide variant
Location: chr11:57712725 (GRCh38)
Gene constraint: LOEUF 0.866 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.38 · 2 PDB

Full TMX2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

neurodevelopmental disorder with microcephaly, cortical malformations, and spasticity — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TMX2 p.Arg205Trp Likely pathogenic ★ same condition
TMX2 p.Ala178Thr Uncertain significance ★ ⚠ same condition
TMX2 p.Arg205Gln Conflicting classifications of pathogenicity ★ ⚠ same condition
TMX2 p.Pro58Leu Uncertain significance ★ ⚠ same condition
TMX2 p.Val160Leu Uncertain significance ★ ⚠ same condition
TMX2 p.Arg53Cys Pathogenic ⚠ same condition
TMX2 p.Gly56Arg Pathogenic ⚠ same condition
TMX2 p.Asp62fs Likely pathogenic ★ 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/tmx2-p-phe36ser (accessed [today's date]).

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