Is POLR1A p.Arg1663= (c.4989G>A) pathogenic?

POLR1A p.Arg1663= (c.4989G>A) is classified Likely benign in POLR1A (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-12-19). Rare (popmax 0.305%, afr).

How common is POLR1A p.Arg1663= (c.4989G>A) in the general population?

POLR1A p.Arg1663= (c.4989G>A) is rare (popmax 0.305%, afr) (gnomAD).

POLR1A p.Arg1663=

c.4989G>A · rs147245488 · VCV785970

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

rare (popmax 0.305%, afr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.097	GERP 2.9, phastCons 0.003
Overall
CADD	8.221	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.305% African / African-American · 229/75,054 alleles

Filtering AF 0.273% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.26%

Overall 0.0154% 248/1,614,232 alleles · rare exomes 120/1,461,886 · genomes 128/152,346 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.305%	328
Remaining individualsnot grpmax-eligible	0.0176%	5,683
Admixed American	0.00833%	12,006
European (non-Finnish)	0.000254%	393,348

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: POLR1A
Protein: p.Arg1663=
Coding: c.4989G>A
MANE Select: NM_015425
dbSNP: rs147245488
Type: single nucleotide variant
Location: chr2:86027958 (GRCh38)
Gene constraint: LOEUF 0.479 · pLI 0.91 (gnomAD)
Structure: AlphaFold pLDDT 80.25 · 7 PDB
Residue 1663: an α-helix; a UniProt-annotated variant site (in afdcin; uncertain significance)

Full POLR1A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

POLR1A p.Arg1663Gln Uncertain significance ★ ⚠ same residue
POLR1A p.Arg1663Trp Uncertain significance ★ ⚠ same residue
POLR1A c.1380+4T>G Uncertain significance ★★ same type
POLR1A p.Ala1478Thr Uncertain significance ★★ ⚠ same type
POLR1A p.Ala1607Thr Uncertain significance ★★ ⚠ same type
POLR1A p.Ala1609Ser Uncertain significance ★★ ⚠ same type
POLR1A p.Ala1617Thr Uncertain significance ★★ ⚠ same type
POLR1A p.Ala343Val 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/polr1a-p-arg1663 (accessed [today's date]).

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