Is POLR1A p.Arg1663Gln (c.4988G>A) pathogenic?

POLR1A p.Arg1663Gln (c.4988G>A) is classified Uncertain significance in POLR1A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-16). AlphaMissense: likely benign (0.062); Very rare (popmax 0.00833%, amr).

How common is POLR1A p.Arg1663Gln (c.4988G>A) in the general population?

POLR1A p.Arg1663Gln (c.4988G>A) is very rare (popmax 0.00833%, amr) (gnomAD).

What do computational predictors say about POLR1A p.Arg1663Gln (c.4988G>A)?

AlphaMissense predicts likely benign (score 0.062) — an in-silico prediction, not a clinical call.

POLR1A p.Arg1663Gln

c.4988G>A · rs753605159 · VCV1897712

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.062 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00833%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.062	likely benign
REVEL	0.085	moderately benign-leaning
SaProt	LLR -5.86	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.24	GERP -0.41, phastCons 0.001
Regional constraint	o/e 0.57	unconstrained · MANE · 1,234 bp · p 1.9e-07 · regional, not allelic
Overall
CADD	14.02	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00833% Admixed American · 5/60,022 alleles

Filtering AF 0.00323% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00206%

Overall 0.00105% 17/1,614,192 alleles · very rare exomes 17/1,461,872 · genomes 0/152,320 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00833%	12,004
South Asian	0.00549%	18,217
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608
African / African-American	0.00133%	75,056
European (non-Finnish)	0.000424%	236,005

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.Arg1663Gln
Coding: c.4988G>A
MANE Select: NM_015425
dbSNP: rs753605159
Type: single nucleotide variant
Location: chr2:86027959 (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.Arg1663= Likely benign ★★ 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-arg1663gln (accessed [today's date]).

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