Is AMT p.Arg331Trp (c.991C>T) pathogenic?

AMT p.Arg331Trp (c.991C>T) is classified Likely pathogenic in AMT (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-29). AlphaMissense: likely pathogenic (0.6858); Very rare (popmax 0.00891%, eas); Associated with glycine encephalopathy.

What condition is associated with AMT p.Arg331Trp (c.991C>T)?

AMT p.Arg331Trp (c.991C>T) is associated with glycine encephalopathy (ClinVar).

How common is AMT p.Arg331Trp (c.991C>T) in the general population?

AMT p.Arg331Trp (c.991C>T) is very rare (popmax 0.00891%, eas) (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.Arg331Trp (c.991C>T)?

AlphaMissense predicts likely pathogenic (score 0.6858) — an in-silico prediction, not a clinical call.

AMT p.Arg331Trp

c.991C>T · rs541011963 · VCV2171612

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6858 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00891%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

glycine encephalopathy

Computational evidence

Protein change
AlphaMissense	0.6858	likely pathogenic ✓ concordant with ClinVar
REVEL	0.913	moderately pathogenic-leaning
SaProt	LLR -15.29	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 3.7	GERP 2.1, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 4,907 bp · p 0.12 · regional, not allelic
Overall
CADD	26.4	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 0.00891% East Asian · 4/44,900 alleles

Filtering AF 0.00298% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00183%

Overall 0.0026% 42/1,613,858 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00891%	11,225
European (non-Finnish)	0.00288%	34,706
Admixed American	0.00167%	59,972
Finnishnot grpmax-eligible	0.00156%	63,948
African / African-American	0.00134%	74,872
South Asian	0.0011%	91,084

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.Arg331Trp
Coding: c.991C>T
MANE Select: NM_000481
dbSNP: rs541011963
Type: single nucleotide variant
Location: chr3:49417860 (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

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 p.Arg331Gln Pathogenic/Likely pathogenic ★★ 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
AMT c.-58C>T Pathogenic/Likely pathogenic ★★ same condition
AMT p.Arg222Cys 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-arg331trp (accessed [today's date]).

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