Is AMT p.Val241Ile (c.721G>A) pathogenic?

AMT p.Val241Ile (c.721G>A) is classified Uncertain significance in AMT (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-10). AlphaMissense: likely benign (0.0912); Very rare (popmax 8.47e-05%, nfe); Associated with glycine encephalopathy.

What condition is associated with AMT p.Val241Ile (c.721G>A)?

AMT p.Val241Ile (c.721G>A) is associated with glycine encephalopathy (ClinVar).

How common is AMT p.Val241Ile (c.721G>A) in the general population?

AMT p.Val241Ile (c.721G>A) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

How is Glycine encephalopathy inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about AMT p.Val241Ile (c.721G>A)?

AlphaMissense predicts likely benign (score 0.0912) — an in-silico prediction, not a clinical call.

AMT p.Val241Ile

c.721G>A · rs1004875097 · VCV1503183

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0912 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

glycine encephalopathy

Computational evidence

Protein change
AlphaMissense	0.0912	likely benign
REVEL	0.284	benign-leaning
SaProt	LLR -8.64	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 0.85	GERP -0.17, phastCons 0.26
Regional constraint	o/e 0.93	unconstrained · MANE · 4,907 bp · p 0.12 · regional, not allelic
Overall
CADD	16.27	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 8.47e-05% European (non-Finnish) · 1/1,179,998 alleles

Overall 0.000657% 1/152,112 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: AMT
Protein: p.Val241Ile
Coding: c.721G>A
MANE Select: NM_000481
dbSNP: rs1004875097
Type: single nucleotide variant
Location: chr3:49419127 (GRCh38)
Gene constraint: LOEUF 0.805 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.66 · 2 PDB
Residue 241: an α-helix

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

Disease context

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

For Glycine encephalopathy (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal
Prevalence: 1-9 / 1 000 000 (Europe)

Similar variants

AMT c.339+2T>C Likely pathogenic ★★ same condition
AMT c.471+2T>C Pathogenic ★★ same condition
AMT c.697-1G>A Likely pathogenic ★★ same condition
AMT c.878-1G>A Pathogenic ★★ same condition
AMT c.91-2A>G Likely pathogenic ★★ same condition
AMT c.-58C>T Pathogenic/Likely pathogenic ★★ same condition
AMT p.Arg222Cys Pathogenic ★★ same condition
AMT p.Arg265Cys Pathogenic/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/amt-p-val241ile (accessed [today's date]).

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