Is GM2A p.Ser189Pro (c.565T>C) pathogenic?

GM2A p.Ser189Pro (c.565T>C) is classified Uncertain significance in GM2A (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-14). AlphaMissense: likely pathogenic (0.8811); Ultra-rare (popmax 0.01%, amr); Associated with Inborn genetic diseases.

What condition is associated with GM2A p.Ser189Pro (c.565T>C)?

GM2A p.Ser189Pro (c.565T>C) is associated with Inborn genetic diseases (ClinVar).

How common is GM2A p.Ser189Pro (c.565T>C) in the general population?

GM2A p.Ser189Pro (c.565T>C) is ultra-rare (popmax 0.01%, amr) (gnomAD).

What do computational predictors say about GM2A p.Ser189Pro (c.565T>C)?

AlphaMissense predicts likely pathogenic (score 0.8811) — an in-silico prediction, not a clinical call.

GM2A p.Ser189Pro

c.565T>C · rs762858957 · VCV2393080

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8811 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.01%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8811	likely pathogenic
REVEL	0.642	indeterminate
SaProt	LLR -7.99	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.83	GERP -1.1, phastCons 0.15
Regional constraint	o/e 1.02	unconstrained · MANE · 14 kb · p 0.75 · regional, not allelic
Overall
CADD	22.5	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 0.01% Admixed American · 6/59,988 alleles

Filtering AF 0.00428% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00295%

Overall 0.000496% 8/1,613,914 alleles · ultra-rare exomes 6/1,461,784 · genomes 2/152,130 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.01%	9,998
African / African-American	0.00133%	74,914
European (non-Finnish)	8.48e-05%	1,179,926

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: GM2A
Protein: p.Ser189Pro
Coding: c.565T>C
MANE Select: NM_000405
dbSNP: rs762858957
Type: single nucleotide variant
Location: chr5:151267434 (GRCh38)
Gene constraint: LOEUF 0.968 · pLI 0.12 (gnomAD)
Structure: AlphaFold pLDDT 89.10 · 8 PDB
Residue 189: a β-strand

Full GM2A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

GM2A p.Arg169His Uncertain significance ★★ ⚠ same condition
GM2A p.Asp116His Uncertain significance ★★ ⚠ same condition
GM2A p.Ile58Phe Uncertain significance ★★ same condition
GM2A p.Leu4Pro Uncertain significance ★★ ⚠ same condition
GM2A p.Pro61Arg Uncertain significance ★★ ⚠ same condition
GM2A p.Tyr168Cys Uncertain significance ★★ ⚠ same condition
GM2A p.Ala19Gly Uncertain significance ★ ⚠ same condition
GM2A p.Asp37Gly 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/gm2a-p-ser189pro (accessed [today's date]).

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