Is GCSH p.Pro28= (c.84G>A) pathogenic?

GCSH p.Pro28= (c.84G>A) is classified Benign/Likely benign in GCSH (ClinVar, Multiple submitters, 7 submitters; last evaluated 2024-11-26). Low-frequency (popmax 3.57%, nfe); Associated with glycine encephalopathy.

What condition is associated with GCSH p.Pro28= (c.84G>A)?

GCSH p.Pro28= (c.84G>A) is associated with glycine encephalopathy (ClinVar).

How common is GCSH p.Pro28= (c.84G>A) in the general population?

GCSH p.Pro28= (c.84G>A) is low-frequency (popmax 3.57%, nfe) (gnomAD).

How is Glycine encephalopathy inherited?

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

GCSH p.Pro28=

c.84G>A · rs775381594 · VCV531790

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

low-frequency (popmax 3.57%, nfe)

Conditions

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 0.038	GERP -3
Overall
CADD	8.633	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 3.57% European (non-Finnish) · 29,810/835,150 alleles

Filtering AF 3.54% ClinGen BA1/BS1 input FAF95, joint · FAF99 3.52%

Overall 3.01% 32,967/1,093,510 alleles · low-frequency

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	3.57%	28
South Asian	2.46%	41
Remaining individualsnot grpmax-eligible	2.42%	41
Middle Eastern	1.86%	54
Ashkenazi Jewishnot grpmax-eligible	1.26%	80
African / African-American	0.722%	138
Finnishnot grpmax-eligible	0.631%	158
Admixed American	0.478%	209
East Asian	0.215%	464

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: GCSH
Protein: p.Pro28=
Coding: c.84G>A
MANE Select: NM_004483
dbSNP: rs775381594
Type: single nucleotide variant
Location: chr16:81096195 (GRCh38)
Gene constraint: LOEUF 1.537 · pLI 0.33 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 85.49 · 3 PDB

Full GCSH 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

GCSH p.Pro28Ser Uncertain significance ★ ⚠ same residue
GCSH p.Gln76Ter Pathogenic/Likely pathogenic ★★ same condition
GCSH p.Met1Val Pathogenic/Likely pathogenic ★★ same condition
GCSH p.Ala11Thr Uncertain significance ★★ ⚠ same condition
GCSH p.Ala2Pro Uncertain significance ★★ ⚠ same condition
GCSH p.Arg17Cys Uncertain significance ★★ ⚠ same condition
GCSH p.Arg7Trp Uncertain significance ★★ ⚠ same condition
GCSH p.Cys26Tyr 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/gcsh-p-pro28 (accessed [today's date]).

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