Is AMT p.Ser77Leu (c.230C>T) pathogenic?

AMT p.Ser77Leu (c.230C>T) is classified Pathogenic/Likely pathogenic in AMT (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-11-15). AlphaMissense: likely pathogenic (0.8035); Very rare (popmax 0.00508%, nfe); Associated with AMT-related disorder.

What condition is associated with AMT p.Ser77Leu (c.230C>T)?

AMT p.Ser77Leu (c.230C>T) is associated with AMT-related disorder, glycine encephalopathy, glycine encephalopathy 1 (ClinVar).

How common is AMT p.Ser77Leu (c.230C>T) in the general population?

AMT p.Ser77Leu (c.230C>T) is very rare (popmax 0.00508%, nfe) (gnomAD).

What do computational predictors say about AMT p.Ser77Leu (c.230C>T)?

AlphaMissense predicts likely pathogenic (score 0.8035) — an in-silico prediction, not a clinical call.

AMT p.Ser77Leu

c.230C>T · rs386833680 · VCV56229

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely pathogenic

0.8035 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00508%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

AMT-related disorder

Computational evidence

Protein change
AlphaMissense	0.8035	likely pathogenic ✓ concordant with ClinVar
REVEL	0.733	pathogenic-leaning
SaProt	LLR -15.51	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 12	GERP 2.1, 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 0.00508% European (non-Finnish) · 60/1,180,038 alleles

Filtering AF 0.00402% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00362%

Overall 0.00428% 69/1,613,686 alleles · very rare

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	0.439%	228
European (non-Finnish)grpmax	0.00508%	19,667
Remaining individualsnot grpmax-eligible	0.0032%	31,242
African / African-American	0.00267%	37,467
South Asian	0.0011%	91,092

Amish 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.Ser77Leu
Coding: c.230C>T
MANE Select: NM_000481
dbSNP: rs386833680
Type: single nucleotide variant
Location: chr3:49422132 (GRCh38)
Gene constraint: LOEUF 0.805 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.66 · 2 PDB
Residue 77: 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

Similar variants

AMT p.Ser77Ter Likely pathogenic ★ same residue
AMT p.Ser77= 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-ser77leu (accessed [today's date]).

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