Is GRK6 p.Ser48Arg (c.144C>A) pathogenic?

GRK6 p.Ser48Arg (c.144C>A) is classified Uncertain significance in GRK6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-30). AlphaMissense: ambiguous (0.3751); Very rare (popmax 0.000509%, nfe).

How common is GRK6 p.Ser48Arg (c.144C>A) in the general population?

GRK6 p.Ser48Arg (c.144C>A) is very rare (popmax 0.000509%, nfe) (gnomAD).

What do computational predictors say about GRK6 p.Ser48Arg (c.144C>A)?

AlphaMissense predicts ambiguous (score 0.3751) — an in-silico prediction, not a clinical call.

GRK6 p.Ser48Arg

c.144C>A · VCV4267219

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3751 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000509%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.3751	ambiguous
REVEL	0.068	moderately benign-leaning
SaProt	LLR -6.89	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.78	GERP 0.84, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 6,349 bp · p 0.0066 · regional, not allelic
Overall
CADD	17.36	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 0.000509% European (non-Finnish) · 6/1,179,368 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000372% 6/1,612,870 alleles · very rare exomes 6/1,460,516 · genomes 0/152,354 · joint denominator

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: GRK6
Protein: p.Ser48Arg
Coding: c.144C>A
MANE Select: NM_001004106
Type: single nucleotide variant
Location: chr5:177430963 (GRCh38)
Gene constraint: LOEUF 0.604 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.22 · 3 PDB
Residue 48: an α-helix; the 'n-terminal' region

Full GRK6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

GRK6 c.*33G>A Uncertain significance ★ same type
GRK6 p.Ala258Val Uncertain significance ★ ⚠ same type
GRK6 p.Ala429Val Uncertain significance ★ ⚠ same type
GRK6 p.Arg123Gln Uncertain significance ★ ⚠ same type
GRK6 p.Arg123Leu Uncertain significance ★ ⚠ same type
GRK6 p.Arg123Trp Uncertain significance ★ ⚠ same type
GRK6 p.Arg169Cys Uncertain significance ★ ⚠ same type
GRK6 p.Arg23Cys 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/grk6-p-ser48arg (accessed [today's date]).

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