Is POLRMT p.Pro604Ser (c.1810C>T) pathogenic?

POLRMT p.Pro604Ser (c.1810C>T) is classified Uncertain significance in POLRMT (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-18). AlphaMissense: ambiguous (0.3927); Very rare (popmax 0.00115%, sas).

How common is POLRMT p.Pro604Ser (c.1810C>T) in the general population?

POLRMT p.Pro604Ser (c.1810C>T) is very rare (popmax 0.00115%, sas) (gnomAD).

What do computational predictors say about POLRMT p.Pro604Ser (c.1810C>T)?

AlphaMissense predicts ambiguous (score 0.3927) — an in-silico prediction, not a clinical call.

POLRMT p.Pro604Ser

c.1810C>T · VCV4141651

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3927 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00115%, sas)

Computational evidence

Protein change
AlphaMissense	0.3927	ambiguous
REVEL	0.523	indeterminate
SaProt	LLR -7.27	tolerated
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 1.16	unconstrained · MANE · 16 kb · p 4.5e-11 · regional, not allelic
Overall
CADD	23.8	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 0.00115% South Asian · 1/87,122 alleles

Overall 6.34e-05% 1/1,577,576 alleles · very rare exomes 1/1,425,246 · genomes 0/152,330 · joint denominator

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.Pro604Ser
Coding: c.1810C>T
MANE Select: NM_005035
Type: single nucleotide variant
Location: chr19:622190 (GRCh38)
Gene constraint: LOEUF 1.26 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.99 · 25 PDB
Residue 604: a UniProt-annotated variant site (in coxpd55); a β-strand

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

Similar variants

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.Arg481Trp 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-pro604ser (accessed [today's date]).

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