Is AMT p.Arg34His (c.101G>A) pathogenic?

AMT p.Arg34His (c.101G>A) is classified Conflicting classifications of pathogenicity in AMT (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-01-28). AlphaMissense: likely benign (0.1036); Rare (popmax 0.313%, mid); Associated with glycine encephalopathy.

What condition is associated with AMT p.Arg34His (c.101G>A)?

AMT p.Arg34His (c.101G>A) is associated with glycine encephalopathy (ClinVar).

How common is AMT p.Arg34His (c.101G>A) in the general population?

AMT p.Arg34His (c.101G>A) is rare (popmax 0.313%, mid) (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.Arg34His (c.101G>A)?

AlphaMissense predicts likely benign (score 0.1036) — an in-silico prediction, not a clinical call.

AMT p.Arg34His

c.101G>A · rs138259479 · VCV531783

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.1036 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.313%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

glycine encephalopathy

Computational evidence

Protein change
AlphaMissense	0.1036	likely benign
REVEL	0.245	benign-leaning
SaProt	LLR -7.96	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 0.63	GERP -1.6, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 4,907 bp · p 0.12 · regional, not allelic
Overall
CADD	21.6	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 0.313% Middle Eastern · 19/6,062 alleles

Filtering AF 0.205% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.171%

Overall 0.0622% 1,004/1,614,046 alleles · rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.662%	151
Middle Easterngrpmax	0.313%	319
Admixed American	0.14%	715
Remaining individualsnot grpmax-eligible	0.0976%	1,025
East Asian	0.0602%	1,662
European (non-Finnish)	0.0506%	1,977
African / African-American	0.0226%	4,415
South Asian	0.00329%	30,363

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg34His
Coding: c.101G>A
MANE Select: NM_000481
dbSNP: rs138259479
Type: single nucleotide variant
Location: chr3:49422261 (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.Arg34Cys Uncertain significance ★★ ⚠ same residue
AMT p.Arg34= Likely benign ★ 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

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-arg34his (accessed [today's date]).

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