Is POLRMT p.Pro808Ser (c.2422C>T) pathogenic?

POLRMT p.Pro808Ser (c.2422C>T) is classified Uncertain significance in POLRMT (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-02). AlphaMissense: likely pathogenic (0.7422); Ultra-rare (popmax 0.0179%, eas).

How common is POLRMT p.Pro808Ser (c.2422C>T) in the general population?

POLRMT p.Pro808Ser (c.2422C>T) is ultra-rare (popmax 0.0179%, eas) (gnomAD).

What do computational predictors say about POLRMT p.Pro808Ser (c.2422C>T)?

AlphaMissense predicts likely pathogenic (score 0.7422) — an in-silico prediction, not a clinical call.

POLRMT p.Pro808Ser

c.2422C>T · VCV4570398

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7422 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0179%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7422	likely pathogenic
REVEL	0.67	pathogenic-leaning
SaProt	LLR -12.83	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
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	26.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0179% East Asian · 8/44,728 alleles

Filtering AF 0.00886% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00805%

Overall 0.00853% 137/1,606,666 alleles · ultra-rare exomes 132/1,454,706 · genomes 5/151,960 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0179%	5,591
European (non-Finnish)	0.0101%	9,898
South Asian	0.00661%	15,140
Remaining individualsnot grpmax-eligible	0.00484%	20,675
African / African-American	0.00134%	74,720

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.Pro808Ser
Coding: c.2422C>T
MANE Select: NM_005035
Type: single nucleotide variant
Location: chr19:621276 (GRCh38)
Gene constraint: LOEUF 1.26 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.99 · 25 PDB
Residue 808: a UniProt-annotated variant site (in coxpd55); the 'mediates interaction with tefm' region; 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-pro808ser (accessed [today's date]).

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