Is POLRMT p.Leu796Val (c.2386C>G) pathogenic?

POLRMT p.Leu796Val (c.2386C>G) is classified Uncertain significance in POLRMT (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-11). AlphaMissense: ambiguous (0.5241); Very rare (popmax 0.000425%, nfe).

How common is POLRMT p.Leu796Val (c.2386C>G) in the general population?

POLRMT p.Leu796Val (c.2386C>G) is very rare (popmax 0.000425%, nfe) (gnomAD).

What do computational predictors say about POLRMT p.Leu796Val (c.2386C>G)?

AlphaMissense predicts ambiguous (score 0.5241) — an in-silico prediction, not a clinical call.

POLRMT p.Leu796Val

c.2386C>G · rs760600753 · VCV2573537

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5241 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000425%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.5241	ambiguous
REVEL	0.288	benign-leaning
SaProt	LLR -10.58	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.7	GERP 0.59, phastCons 1
Regional constraint	o/e 1.16	unconstrained · MANE · 16 kb · p 4.5e-11 · regional, not allelic
Overall
CADD	22.8	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 0.000425% European (non-Finnish) · 5/1,176,876 alleles

Filtering AF 0.000125% ClinGen BA1/BS1 input FAF95, joint · FAF99 9.1e-05%

Overall 0.000313% 5/1,597,994 alleles · very rare exomes 5/1,445,852 · genomes 0/152,142 · 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.Leu796Val
Coding: c.2386C>G
MANE Select: NM_005035
dbSNP: rs760600753
Type: single nucleotide variant
Location: chr19:621312 (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.Leu796Pro 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-leu796val (accessed [today's date]).

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