Is AMT p.Arg381Gln (c.1142G>A) pathogenic?

AMT p.Arg381Gln (c.1142G>A) is classified Uncertain significance in AMT (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-05-07). AlphaMissense: ambiguous (0.455); Ultra-rare (popmax 0.066%, mid); Associated with Inborn genetic diseases.

What condition is associated with AMT p.Arg381Gln (c.1142G>A)?

AMT p.Arg381Gln (c.1142G>A) is associated with Inborn genetic diseases, glycine encephalopathy (ClinVar).

How common is AMT p.Arg381Gln (c.1142G>A) in the general population?

AMT p.Arg381Gln (c.1142G>A) is ultra-rare (popmax 0.066%, mid) (gnomAD).

What do computational predictors say about AMT p.Arg381Gln (c.1142G>A)?

AlphaMissense predicts ambiguous (score 0.455) — an in-silico prediction, not a clinical call.

AMT p.Arg381Gln

c.1142G>A · rs771853703 · VCV2044611

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.455 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.066%, mid)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.455	ambiguous
REVEL	0.845	moderately pathogenic-leaning
SaProt	LLR -13.61	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 4,907 bp · p 0.12 · regional, not allelic
Overall
CADD	33.0	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 0.066% Middle Eastern · 4/6,062 alleles

Filtering AF 0.0225% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0135%

Overall 0.00279% 45/1,614,168 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.066%	1,516
Remaining individualsnot grpmax-eligible	0.008%	12,502
East Asian	0.00446%	22,442
European (non-Finnish)	0.00263%	38,066
South Asian	0.0022%	45,544
Finnishnot grpmax-eligible	0.00156%	64,026

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.Arg381Gln
Coding: c.1142G>A
MANE Select: NM_000481
dbSNP: rs771853703
Type: single nucleotide variant
Location: chr3:49417610 (GRCh38)
Gene constraint: LOEUF 0.805 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.66 · 2 PDB

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: glycine encephalopathy

Similar variants

AMT p.Arg381= Uncertain significance ★ same residue
AMT p.Arg381Trp Uncertain significance ★ ⚠ same residue
AMT p.Arg381Leu Uncertain significance ⚠ 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-arg381gln (accessed [today's date]).

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