Is GRM1 p.Pro1165= (c.3495C>A) pathogenic?

GRM1 p.Pro1165= (c.3495C>A) is classified Benign in GRM1 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-02-03). Common (popmax 67.5%, afr) — too common for a highly-penetrant pathogenic allele; Associated with spinocerebellar ataxia 44.

What condition is associated with GRM1 p.Pro1165= (c.3495C>A)?

GRM1 p.Pro1165= (c.3495C>A) is associated with spinocerebellar ataxia 44, autosomal recessive spinocerebellar ataxia 13 (ClinVar).

How is Spinocerebellar ataxia type 44 inherited?

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

GRM1 p.Pro1165=

Q: How common is GRM1 p.Pro1165= (c.3495C>A) in the general population?

GRM1 p.Pro1165= (c.3495C>A) is common (popmax 67.5%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.3495C>A · rs9373491 · VCV129213

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

gnomAD v4.1

Common

common (popmax 67.5%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

spinocerebellar ataxia 44

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 -3.5
Overall
CADD	0.312	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 67.5% African / African-American · 50,570/74,962 alleles

Filtering AF 67% ClinGen BA1/BS1 input FAF95, joint · FAF99 66.8%

Overall 52.9% 847,637/1,602,804 alleles · common exomes 762,612/1,450,680 · genomes 85,025/152,124 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	67.5%	1
South Asian	60%	2
Ashkenazi Jewishnot grpmax-eligible	56.8%	2
Middle Eastern	56.6%	2
Remaining individualsnot grpmax-eligible	54.2%	2
European (non-Finnish)	52.2%	2
East Asian	49.9%	2
Amishnot grpmax-eligible	47.1%	2
Finnishnot grpmax-eligible	44.7%	2
Admixed American	42.7%	2

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: GRM1
Protein: p.Pro1165=
Coding: c.3495C>A
MANE Select: NM_001278064
dbSNP: rs9373491
Type: single nucleotide variant
Location: chr6:146434706 (GRCh38)
Gene constraint: LOEUF 0.417 · pLI 1.00 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 71.38 · 8 PDB
Residue 1165: the 'disordered' region

Full GRM1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

spinocerebellar ataxia 44 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: autosomal recessive spinocerebellar ataxia 13

For Spinocerebellar ataxia type 44 (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

GRM1 c.951-6T>A Uncertain significance ★★ same condition
GRM1 p.Arg358Lys Uncertain significance ★★ ⚠ same condition
GRM1 p.Asn389His Uncertain significance ★★ ⚠ same condition
GRM1 p.Leu277Ile Uncertain significance ★★ ⚠ same condition
GRM1 p.Lys276Thr Uncertain significance ★★ ⚠ same condition
GRM1 p.Pro970Leu Uncertain significance ★★ ⚠ same condition
GRM1 p.Ala788= Benign/Likely benign ★★ same condition
GRM1 p.Arg681= Benign/Likely benign ★★ 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/grm1-p-pro1165 (accessed [today's date]).

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