Is GRK5 p.Arg361Ser (c.1083G>T) pathogenic?

GRK5 p.Arg361Ser (c.1083G>T) is classified Uncertain significance in GRK5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-11). AlphaMissense: likely pathogenic (0.5921); Ultra-rare (popmax 0.0161%, nfe).

How common is GRK5 p.Arg361Ser (c.1083G>T) in the general population?

GRK5 p.Arg361Ser (c.1083G>T) is ultra-rare (popmax 0.0161%, nfe) (gnomAD).

What do computational predictors say about GRK5 p.Arg361Ser (c.1083G>T)?

AlphaMissense predicts likely pathogenic (score 0.5921) — an in-silico prediction, not a clinical call.

GRK5 p.Arg361Ser

c.1083G>T · rs116059103 · VCV2222865

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5921 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0161%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.5921	likely pathogenic
REVEL	0.126	moderately benign-leaning
SaProt	LLR -9.48	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.22	GERP -3.7, phastCons 0.75
Regional constraint	o/e 0.79	unconstrained · MANE · 247 kb · p 4.3e-09 · regional, not allelic
Overall
CADD	19.36	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 0.0161% European (non-Finnish) · 190/1,177,772 alleles

Filtering AF 0.0142% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0135%

Overall 0.0121% 195/1,611,300 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0161%	6,199
Remaining individualsnot grpmax-eligible	0.00481%	20,783
African / African-American	0.00267%	37,509

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: GRK5
Protein: p.Arg361Ser
Coding: c.1083G>T
MANE Select: NM_005308
dbSNP: rs116059103
Type: single nucleotide variant
Location: chr10:119443569 (GRCh38)
Gene constraint: LOEUF 0.604 · pLI 0.04 (gnomAD)
Structure: AlphaFold pLDDT 90.75 · 23 PDB
Residue 361: the protein kinase domain

Full GRK5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

GRK5 c.440+10G>A Likely benign ★★ same type
GRK5 c.440+9C>T Benign ★★ same type
GRK5 p.Ala119Val Benign ★★ ⚠ same type
GRK5 p.Leu141Ile Benign ★★ same type
GRK5 p.Phe448Leu Benign ★★ same type
GRK5 p.Ala471Thr Uncertain significance ★ ⚠ same type
GRK5 p.Arg169His Uncertain significance ★ ⚠ same type
GRK5 p.Arg206Trp Uncertain significance ★ ⚠ same type

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/grk5-p-arg361ser (accessed [today's date]).

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