Is GRM1 p.Ser993Pro (c.2977T>C) pathogenic?

GRM1 p.Ser993Pro (c.2977T>C) is classified Benign in GRM1 (ClinVar, Multiple submitters, 10 submitters; last evaluated 2026-02-03). AlphaMissense: likely benign (0.0558); Common (popmax 70.6%, afr) — too common for a highly-penetrant pathogenic allele; Associated with spinocerebellar ataxia 44.

What condition is associated with GRM1 p.Ser993Pro (c.2977T>C)?

GRM1 p.Ser993Pro (c.2977T>C) 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.

What do computational predictors say about GRM1 p.Ser993Pro (c.2977T>C)?

AlphaMissense predicts likely benign (score 0.0558) — an in-silico prediction, not a clinical call.

GRM1 p.Ser993Pro

Q: How common is GRM1 p.Ser993Pro (c.2977T>C) in the general population?

GRM1 p.Ser993Pro (c.2977T>C) is common (popmax 70.6%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.2977T>C · rs6923492 · VCV129210

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

AlphaMissense

likely benign

0.0558 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 70.6%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

spinocerebellar ataxia 44

Computational evidence

Protein change
AlphaMissense	0.0558	likely benign
REVEL	0.218	benign-leaning
SaProt	LLR -5.28	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.1	GERP -2.3, phastCons 0.06
Regional constraint	o/e 1.11	unconstrained · MANE · 35 kb · p 0.039 · regional, not allelic
Overall
CADD	10.72	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 70.6% African / African-American · 52,891/74,950 alleles

Filtering AF 70.1% ClinGen BA1/BS1 input FAF95, joint · FAF99 69.9%

Overall 53.1% 855,473/1,612,248 alleles · common exomes 769,036/1,460,160 · genomes 86,437/152,088 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	70.6%	1
South Asian	60%	2
Middle Eastern	57.1%	2
Ashkenazi Jewishnot grpmax-eligible	56.7%	2
Remaining individualsnot grpmax-eligible	54.5%	2
European (non-Finnish)	52.3%	2
East Asian	49.7%	2
Amishnot grpmax-eligible	47.4%	2
Finnishnot grpmax-eligible	44.9%	2
Admixed American	43%	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.Ser993Pro
Coding: c.2977T>C
MANE Select: NM_001278064
dbSNP: rs6923492
Type: single nucleotide variant
Location: chr6:146434188 (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 993: a UniProt-annotated variant site (in)

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-ser993pro (accessed [today's date]).

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