Is POLRMT p.Arg481Pro (c.1442G>C) pathogenic?

POLRMT p.Arg481Pro (c.1442G>C) is classified Uncertain significance in POLRMT (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-13). AlphaMissense: ambiguous (0.371); Rare (popmax 0.93%, afr).

How common is POLRMT p.Arg481Pro (c.1442G>C) in the general population?

POLRMT p.Arg481Pro (c.1442G>C) is rare (popmax 0.93%, afr) (gnomAD).

What do computational predictors say about POLRMT p.Arg481Pro (c.1442G>C)?

AlphaMissense predicts ambiguous (score 0.371) — an in-silico prediction, not a clinical call.

POLRMT p.Arg481Pro

c.1442G>C · VCV4141616

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.371 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.93%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.371	ambiguous
REVEL	0.107	moderately benign-leaning
SaProt	LLR -8.96	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -3.3	GERP -3.3
Regional constraint	o/e 1.16	unconstrained · MANE · 16 kb · p 4.5e-11 · regional, not allelic
Overall
CADD	2.59	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 0.93% African / African-American · 694/74,618 alleles

Filtering AF 0.873% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.85%

Overall 0.0544% 868/1,596,924 alleles · rare exomes 427/1,444,604 · genomes 441/152,320 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.93%	108
Admixed American	0.0865%	1,156
Remaining individualsnot grpmax-eligible	0.0599%	1,668
Middle Eastern	0.037%	2,705
European (non-Finnish)	0.00708%	14,129
South Asian	0.00225%	44,448

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: POLRMT
Protein: p.Arg481Pro
Coding: c.1442G>C
MANE Select: NM_005035
Type: single nucleotide variant
Location: chr19:622834 (GRCh38)
Gene constraint: LOEUF 1.26 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.99 · 25 PDB
Residue 481: a UniProt-annotated variant site (in coxpd55); an α-helix

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

Similar variants

POLRMT p.Arg481Trp Uncertain significance ★★ ⚠ same residue
POLRMT p.Gln681Ter Pathogenic/Likely pathogenic ★★ same type
POLRMT p.Ala409Val Uncertain significance ★★ ⚠ same type
POLRMT p.Ala444Val Uncertain significance ★★ ⚠ same type
POLRMT p.Arg165Trp Uncertain significance ★★ ⚠ same type
POLRMT p.Arg447Gln Uncertain significance ★★ ⚠ same type
POLRMT p.Arg759His Uncertain significance ★★ ⚠ same type
POLRMT p.Arg90Gln 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/polrmt-p-arg481pro (accessed [today's date]).

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