Is MTR p.Ile72Val (c.214A>G) pathogenic?

MTR p.Ile72Val (c.214A>G) is classified Uncertain significance in MTR (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-24). AlphaMissense: likely benign (0.0844); Very rare (popmax 0.005%, amr).

How common is MTR p.Ile72Val (c.214A>G) in the general population?

MTR p.Ile72Val (c.214A>G) is very rare (popmax 0.005%, amr) (gnomAD).

What do computational predictors say about MTR p.Ile72Val (c.214A>G)?

AlphaMissense predicts likely benign (score 0.0844) — an in-silico prediction, not a clinical call.

MTR p.Ile72Val

c.214A>G · VCV4881618

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0844 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0844	likely benign
REVEL	0.074	moderately benign-leaning
SaProt	LLR -4.46	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.9	GERP 0.34, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 102 kb · p 9.3e-14 · regional, not allelic
Overall
CADD	20.5	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 0.005% Admixed American · 3/60,004 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.00031% 5/1,614,104 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	20,001
European (non-Finnish)	0.000169%	590,012

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.Ile72Val
Coding: c.214A>G
MANE Select: NM_000254
Type: single nucleotide variant
Location: chr1:236803607 (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 72: the hcy-binding domain; an α-helix

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

Similar variants

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
MTR p.Arg1147Ter Pathogenic ★★ same type
MTR p.Arg585Ter 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-ile72val (accessed [today's date]).

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