Is POLK p.Arg63Gln (c.188G>A) pathogenic?

POLK p.Arg63Gln (c.188G>A) is classified Uncertain significance in POLK (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-29). AlphaMissense: likely benign (0.2658); Very rare (popmax 0.00668%, afr).

How common is POLK p.Arg63Gln (c.188G>A) in the general population?

POLK p.Arg63Gln (c.188G>A) is very rare (popmax 0.00668%, afr) (gnomAD).

What do computational predictors say about POLK p.Arg63Gln (c.188G>A)?

AlphaMissense predicts likely benign (score 0.2658) — an in-silico prediction, not a clinical call.

POLK p.Arg63Gln

c.188G>A · VCV4141321

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2658 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00668%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2658	likely benign
REVEL	0.381	indeterminate
SaProt	LLR -10.06	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.4, phastCons 1
Overall
CADD	33.0	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 0.00668% African / African-American · 5/74,802 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00162%

Overall 0.000434% 7/1,612,266 alleles · very rare exomes 5/1,460,270 · genomes 2/151,996 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00668%	14,960
South Asian	0.0011%	90,874
European (non-Finnish)	8.48e-05%	1,179,103

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: POLK
Protein: p.Arg63Gln
Coding: c.188G>A
MANE Select: NM_016218
Type: single nucleotide variant
Location: chr5:75552524 (GRCh38)
Gene constraint: LOEUF 0.924 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.62 · 19 PDB
Residue 63: an α-helix

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

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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/polk-p-arg63gln (accessed [today's date]).

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