Is GRK4 p.Ser40Arg (c.118A>C) pathogenic?

GRK4 p.Ser40Arg (c.118A>C) is classified Uncertain significance in GRK4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-16). AlphaMissense: likely benign (0.2229); Absent from gnomAD v4.1.

How common is GRK4 p.Ser40Arg (c.118A>C) in the general population?

GRK4 p.Ser40Arg (c.118A>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about GRK4 p.Ser40Arg (c.118A>C)?

AlphaMissense predicts likely benign (score 0.2229) — an in-silico prediction, not a clinical call.

GRK4 p.Ser40Arg

c.118A>C · rs2474770046 · VCV3102597

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2229 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2229	likely benign
REVEL	0.121	moderately benign-leaning
SaProt	LLR -11.06	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.6	GERP 1.4, phastCons 0.99
Regional constraint	o/e 1.04	unconstrained · MANE · 77 kb · p 0.28 · regional, not allelic
Overall
CADD	21.5	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: GRK4
Protein: p.Ser40Arg
Coding: c.118A>C
MANE Select: NM_182982
dbSNP: rs2474770046
Type: single nucleotide variant
Location: chr4:2984578 (GRCh38)
Gene constraint: LOEUF 1.262 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.80 · 1 PDB
Residue 40: a turn; the 'n-terminal' region

Full GRK4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

GRK4 p.Gln173Ter Benign ★★ same type
GRK4 p.Ala203Thr Uncertain significance ★ ⚠ same type
GRK4 p.Ala259Gly Uncertain significance ★ ⚠ same type
GRK4 p.Ala334Gly Uncertain significance ★ same type
GRK4 p.Ala86Thr Uncertain significance ★ ⚠ same type
GRK4 p.Arg108Lys Uncertain significance ★ ⚠ same type
GRK4 p.Arg207Gln Uncertain significance ★ ⚠ same type
GRK4 p.Arg226Lys 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/grk4-p-ser40arg (accessed [today's date]).

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