Is POLR1A p.Arg1663Trp (c.4987C>T) pathogenic?

POLR1A p.Arg1663Trp (c.4987C>T) is classified Uncertain significance in POLR1A (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-23). AlphaMissense: likely benign (0.1608); Very rare (popmax 0.00267%, afr); Associated with Inborn genetic diseases.

What condition is associated with POLR1A p.Arg1663Trp (c.4987C>T)?

POLR1A p.Arg1663Trp (c.4987C>T) is associated with Inborn genetic diseases (ClinVar).

How common is POLR1A p.Arg1663Trp (c.4987C>T) in the general population?

POLR1A p.Arg1663Trp (c.4987C>T) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about POLR1A p.Arg1663Trp (c.4987C>T)?

AlphaMissense predicts likely benign (score 0.1608) — an in-silico prediction, not a clinical call.

POLR1A p.Arg1663Trp

c.4987C>T · rs765177457 · VCV3216439

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1608 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1608	likely benign
REVEL	0.52	indeterminate
SaProt	LLR -9.10	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.5	GERP 5.3, phastCons 1
Regional constraint	o/e 0.57	unconstrained · MANE · 1,234 bp · p 1.9e-07 · regional, not allelic
Overall
CADD	29.4	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 0.00267% African / African-American · 2/74,926 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000434% 7/1,614,080 alleles · very rare exomes 6/1,461,870 · genomes 1/152,210 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,463
South Asian	0.0011%	91,090
European (non-Finnish)	0.000339%	295,009

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.Arg1663Trp
Coding: c.4987C>T
MANE Select: NM_015425
dbSNP: rs765177457
Type: single nucleotide variant
Location: chr2:86027960 (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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

POLR1A p.Arg1663= Likely benign ★★ same residue
POLR1A p.Arg1663Gln Uncertain significance ★ ⚠ same residue
POLR1A p.Ala1478Thr Uncertain significance ★★ ⚠ same condition
POLR1A p.Ala1609Ser Uncertain significance ★★ ⚠ same condition
POLR1A p.Ala1617Thr Uncertain significance ★★ ⚠ same condition
POLR1A p.Ala343Val Uncertain significance ★★ ⚠ same condition
POLR1A p.Ala529Thr Uncertain significance ★★ ⚠ same condition
POLR1A p.Ala752Ser Uncertain significance ★★ ⚠ same condition

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-arg1663trp (accessed [today's date]).

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