Is AMT p.Arg320His (c.959G>A) pathogenic?

AMT p.Arg320His (c.959G>A) is classified Pathogenic in AMT (ClinVar, Multiple submitters, 20 submitters; last evaluated 2026-04-01). AlphaMissense: likely pathogenic (0.7683); Ultra-rare (popmax 0.0105%, nfe); Associated with AMT-related disorder.

What condition is associated with AMT p.Arg320His (c.959G>A)?

AMT p.Arg320His (c.959G>A) is associated with AMT-related disorder, glycine encephalopathy, glycine encephalopathy 1 (ClinVar).

How common is AMT p.Arg320His (c.959G>A) in the general population?

AMT p.Arg320His (c.959G>A) is ultra-rare (popmax 0.0105%, nfe) (gnomAD).

What do computational predictors say about AMT p.Arg320His (c.959G>A)?

AlphaMissense predicts likely pathogenic (score 0.7683) — an in-silico prediction, not a clinical call.

AMT p.Arg320His

c.959G>A · rs121964985 · VCV11979

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 20 submitters

AlphaMissense

likely pathogenic

0.7683 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0105%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

AMT-related disorder

Computational evidence

Protein change
AlphaMissense	0.7683	likely pathogenic ✓ concordant with ClinVar
REVEL	0.927	moderately pathogenic-leaning
SaProt	LLR -15.54	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.1, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 4,907 bp · p 0.12 · 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 0.0105% European (non-Finnish) · 124/1,180,038 alleles

Filtering AF 0.009% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00842%

Overall 0.00799% 129/1,613,956 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0105%	9,516
Remaining individualsnot grpmax-eligible	0.0048%	20,826
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,604
South Asian	0.0011%	91,082

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.Arg320His
Coding: c.959G>A
MANE Select: NM_000481
dbSNP: rs121964985
Type: single nucleotide variant
Location: chr3:49417892 (GRCh38)
Gene constraint: LOEUF 0.805 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.66 · 2 PDB
Residue 320: a UniProt-annotated variant site (in gce2; loss of aminomethyltransferase activity); a β-strand

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

Disease context

AMT-related disorder

Also linked: glycine encephalopathy glycine encephalopathy 1 glycine encephalopathy 2

Similar variants

AMT p.Arg320Gly Likely pathogenic ★★ same residue
AMT p.Arg320Leu Uncertain significance ★★ ⚠ same residue
AMT p.Arg320Cys Conflicting classifications of pathogenicity ★ same residue
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

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-arg320his (accessed [today's date]).

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