Is SLC6A9 p.Ser136= (c.408G>A) pathogenic?

SLC6A9 p.Ser136= (c.408G>A) is classified Likely benign in SLC6A9 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-24). Very rare (popmax 0.005%, amr); Associated with atypical glycine encephalopathy.

What condition is associated with SLC6A9 p.Ser136= (c.408G>A)?

SLC6A9 p.Ser136= (c.408G>A) is associated with atypical glycine encephalopathy (ClinVar).

How common is SLC6A9 p.Ser136= (c.408G>A) in the general population?

SLC6A9 p.Ser136= (c.408G>A) is very rare (popmax 0.005%, amr) (gnomAD).

How is Glycine encephalopathy inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

SLC6A9 p.Ser136=

c.408G>A · rs201088849 · VCV2060597

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Conditions

atypical glycine encephalopathy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -15	GERP -3.9
Overall
CADD	0.444	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.005% Admixed American · 3/59,990 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.00112% 18/1,613,822 alleles · very rare exomes 17/1,461,860 · genomes 1/151,962 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	19,997
East Asian	0.00446%	22,439
Remaining individualsnot grpmax-eligible	0.0016%	62,482
European (non-Finnish)	0.00102%	98,335

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: SLC6A9
Protein: p.Ser136=
Coding: c.408G>A
MANE Select: NM_001024845
dbSNP: rs201088849
Type: single nucleotide variant
Location: chr1:44008535 (GRCh38)
Gene constraint: LOEUF 0.544 · pLI 0.51 (gnomAD)
Structure: AlphaFold pLDDT 81.95 · 9 PDB
Residue 136: an α-helix

Full SLC6A9 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

atypical 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

SLC6A9 p.Ser136Leu Uncertain significance ★★ ⚠ same residue
SLC6A9 c.1536+1G>A Likely pathogenic ★★ same condition
SLC6A9 p.Gln278Ter Pathogenic/Likely pathogenic ★★ same condition
SLC6A9 c.31-6226C>T Uncertain significance ★★ ⚠ same condition
SLC6A9 c.31-731A>C Uncertain significance ★★ ⚠ same condition
SLC6A9 c.31-825G>A Uncertain significance ★★ ⚠ same condition
SLC6A9 p.Ala538Val Uncertain significance ★★ ⚠ same condition
SLC6A9 p.Arg260His Uncertain significance ★★ ⚠ 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/slc6a9-p-ser136 (accessed [today's date]).

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