Is MTX1 p.Pro69Ser (c.205C>T) pathogenic?

MTX1 p.Pro69Ser (c.205C>T) is classified Uncertain significance in MTX1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-21). AlphaMissense: likely benign (0.0763); Ultra-rare (popmax 0.0107%, nfe).

How common is MTX1 p.Pro69Ser (c.205C>T) in the general population?

MTX1 p.Pro69Ser (c.205C>T) is ultra-rare (popmax 0.0107%, nfe) (gnomAD).

What do computational predictors say about MTX1 p.Pro69Ser (c.205C>T)?

AlphaMissense predicts likely benign (score 0.0763) — an in-silico prediction, not a clinical call.

MTX1 p.Pro69Ser

c.205C>T · VCV3914532

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0763 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0107%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0763	likely benign
REVEL	0.083	moderately benign-leaning
SaProt	LLR -6.33	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 -2.7	GERP -3.2
Regional constraint	o/e 1.11	unconstrained · MANE · 3,353 bp · p 0.053 · regional, not allelic
Overall
CADD	2.627	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 0.0107% European (non-Finnish) · 125/1,170,424 alleles

Filtering AF 0.00913% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00851%

Overall 0.00817% 130/1,591,156 alleles · ultra-rare exomes 123/1,438,934 · genomes 7/152,222 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0107%	9,363
Remaining individualsnot grpmax-eligible	0.0065%	15,376
Admixed American	0.00175%	56,990

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: MTX1
Protein: p.Pro69Ser
Coding: c.205C>T
MANE Select: NM_002455
Type: single nucleotide variant
Location: chr1:155209009 (GRCh38)
Gene constraint: LOEUF 0.899 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.83
Residue 69: the 'disordered' region

Full MTX1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MTX1 c.528+101G>C Uncertain significance ★ same type
MTX1 c.528+169G>T Uncertain significance ★ same type
MTX1 c.528+260T>C Uncertain significance ★ same type
MTX1 c.528+289C>T Uncertain significance ★ same type
MTX1 c.528+307G>A Uncertain significance ★ same type
MTX1 c.528+35T>C Uncertain significance ★ same type
MTX1 p.Ala71Gly Uncertain significance ★ ⚠ same type
MTX1 p.Arg38Leu 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/mtx1-p-pro69ser (accessed [today's date]).

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