Is MTR p.Ala129Pro (c.385G>C) pathogenic?

MTR p.Ala129Pro (c.385G>C) is classified Likely pathogenic in MTR (ClinVar, No assertion criteria, 1 submitter). AlphaMissense: likely pathogenic (0.9629); Very rare (popmax 0.000593%, nfe); Associated with homocystinuria.

What condition is associated with MTR p.Ala129Pro (c.385G>C)?

MTR p.Ala129Pro (c.385G>C) is associated with homocystinuria (ClinVar).

How common is MTR p.Ala129Pro (c.385G>C) in the general population?

MTR p.Ala129Pro (c.385G>C) is very rare (popmax 0.000593%, nfe) (gnomAD).

What do computational predictors say about MTR p.Ala129Pro (c.385G>C)?

AlphaMissense predicts likely pathogenic (score 0.9629) — an in-silico prediction, not a clinical call.

MTR p.Ala129Pro

c.385G>C · rs1190777785 · VCV812985

Likely pathogenic No assertion criteria

Classification

Likely pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9629 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000593%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

homocystinuria

Computational evidence

Protein change
AlphaMissense	0.9629	likely pathogenic ✓ concordant with ClinVar
REVEL	0.477	indeterminate
SaProt	LLR -15.31	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.5, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 102 kb · p 9.3e-14 · regional, not allelic
Overall
CADD	32.0	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 0.000593% European (non-Finnish) · 7/1,180,034 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000434% 7/1,614,080 alleles · very rare

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: MTR
Protein: p.Ala129Pro
Coding: c.385G>C
MANE Select: NM_000254
dbSNP: rs1190777785
Type: single nucleotide variant
Location: chr1:236808749 (GRCh38)
Gene constraint: LOEUF 0.625 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 87.60 · 9 PDB
Residue 129: the hcy-binding domain; an α-helix

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

Disease context

homocystinuria — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MTR p.Ala129= Likely benign ★ same residue
MTR p.Pro1173Leu Pathogenic/Likely pathogenic ★★ ⚠ same condition
MTR c.1812+1G>A Likely pathogenic ★★ same type
MTR c.2474-1G>C Pathogenic ★★ same type
MTR c.2595-2A>G Likely pathogenic ★★ same type
MTR c.340-166A>G Pathogenic/Likely pathogenic ★★ same type
MTR c.609+1088G>A Pathogenic ★★ same type
MTR c.866-2A>C Pathogenic/Likely pathogenic ★★ 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/mtr-p-ala129pro (accessed [today's date]).

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