Is TMX1 p.Pro3Ser (c.7C>T) pathogenic?

TMX1 p.Pro3Ser (c.7C>T) is classified Uncertain significance in TMX1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-20). AlphaMissense: likely benign (0.0694); Very rare (popmax 0.00297%, nfe).

How common is TMX1 p.Pro3Ser (c.7C>T) in the general population?

TMX1 p.Pro3Ser (c.7C>T) is very rare (popmax 0.00297%, nfe) (gnomAD).

What do computational predictors say about TMX1 p.Pro3Ser (c.7C>T)?

AlphaMissense predicts likely benign (score 0.0694) — an in-silico prediction, not a clinical call.

TMX1 p.Pro3Ser

c.7C>T · VCV4187708

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0694 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00297%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0694	likely benign
REVEL	0.033	moderately benign-leaning
SaProt	LLR -6.58	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.3	GERP -0.44, phastCons 0.98
Regional constraint	o/e 1.02	unconstrained · MANE · 14 kb · p 0.69 · regional, not allelic
Overall
CADD	20.9	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 0.00297% European (non-Finnish) · 35/1,179,560 alleles

Filtering AF 0.00215% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00191%

Overall 0.00236% 38/1,610,684 alleles · very rare exomes 37/1,458,418 · genomes 1/152,266 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00297%	33,702
Admixed American	0.00167%	59,974
Remaining individualsnot grpmax-eligible	0.0016%	62,360
African / African-American	0.00133%	74,916

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: TMX1
Protein: p.Pro3Ser
Coding: c.7C>T
MANE Select: NM_030755
Type: single nucleotide variant
Location: chr14:51240299 (GRCh38)
Gene constraint: LOEUF 1.01 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.95 · 1 PDB

Full TMX1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TMX1 p.Leu158= Likely benign ★★ same type
TMX1 p.Ala203Thr Uncertain significance ★ ⚠ same type
TMX1 p.Ala58Thr Uncertain significance ★ ⚠ same type
TMX1 p.Ala8Gly Uncertain significance ★ ⚠ same type
TMX1 p.Arg212His Uncertain significance ★ ⚠ same type
TMX1 p.Cys198Trp Uncertain significance ★ ⚠ same type
TMX1 p.Gln157Arg Uncertain significance ★ ⚠ same type
TMX1 p.Gln268Glu 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/tmx1-p-pro3ser (accessed [today's date]).

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