Is POLRMT p.Leu796Pro (c.2387T>C) pathogenic?

POLRMT p.Leu796Pro (c.2387T>C) is classified Uncertain significance in POLRMT (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-07). AlphaMissense: likely pathogenic (0.9692); Very rare (popmax 0.00224%, eas).

How common is POLRMT p.Leu796Pro (c.2387T>C) in the general population?

POLRMT p.Leu796Pro (c.2387T>C) is very rare (popmax 0.00224%, eas) (gnomAD).

What do computational predictors say about POLRMT p.Leu796Pro (c.2387T>C)?

AlphaMissense predicts likely pathogenic (score 0.9692) — an in-silico prediction, not a clinical call.

POLRMT p.Leu796Pro

c.2387T>C · VCV4886644

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9692 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00224%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9692	likely pathogenic · top 6% in POLRMT
REVEL	0.661	pathogenic-leaning
SaProt	LLR -12.96	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP 1.8, phastCons 1
Regional constraint	o/e 1.16	unconstrained · MANE · 16 kb · p 4.5e-11 · regional, not allelic
Overall
CADD	27.2	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 0.00224% East Asian · 1/44,622 alleles

Filtering AF 0.000765% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000607%

Overall 0.00106% 17/1,599,536 alleles · very rare exomes 15/1,447,526 · genomes 2/152,010 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00224%	44,622
African / African-American	0.00134%	74,654
European (non-Finnish)	0.00127%	78,476

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.Leu796Pro
Coding: c.2387T>C
MANE Select: NM_005035
Type: single nucleotide variant
Location: chr19:621311 (GRCh38)
Gene constraint: LOEUF 1.26 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.99 · 25 PDB
Residue 796: a UniProt-annotated variant site (in coxpd55)

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

Similar variants

POLRMT p.Leu796Val 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.Arg481Trp Uncertain significance ★★ ⚠ same type
POLRMT p.Arg759His 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-leu796pro (accessed [today's date]).

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