Is POLRMT p.Pro741Arg (c.2222C>G) pathogenic?

POLRMT p.Pro741Arg (c.2222C>G) is classified Uncertain significance in POLRMT (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-13). AlphaMissense: likely benign (0.1667); Ultra-rare (popmax 0.0201%, afr); Associated with combined oxidative phosphorylation deficiency 55.

What condition is associated with POLRMT p.Pro741Arg (c.2222C>G)?

POLRMT p.Pro741Arg (c.2222C>G) is associated with combined oxidative phosphorylation deficiency 55 (ClinVar).

How common is POLRMT p.Pro741Arg (c.2222C>G) in the general population?

POLRMT p.Pro741Arg (c.2222C>G) is ultra-rare (popmax 0.0201%, afr) (gnomAD).

What do computational predictors say about POLRMT p.Pro741Arg (c.2222C>G)?

AlphaMissense predicts likely benign (score 0.1667) — an in-silico prediction, not a clinical call.

POLRMT p.Pro741Arg

c.2222C>G · VCV4141620

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1667 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0201%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

combined oxidative phosphorylation deficiency 55

Computational evidence

Protein change
AlphaMissense	0.1667	likely benign
REVEL	0.178	moderately benign-leaning
SaProt	LLR -6.68	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.7	GERP 1.8, phastCons 1
Regional constraint	o/e 1.16	unconstrained · MANE · 16 kb · p 4.5e-11 · regional, not allelic
Overall
CADD	23.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0201% African / African-American · 13/64,606 alleles

Filtering AF 0.0119% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00941%

Overall 0.00102% 14/1,368,370 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0201%	4,970
Remaining individualsnot grpmax-eligible	0.00192%	52,156

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.Pro741Arg
Coding: c.2222C>G
MANE Select: NM_005035
Type: single nucleotide variant
Location: chr19:621476 (GRCh38)
Gene constraint: LOEUF 1.26 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.99 · 25 PDB
Residue 741: a UniProt-annotated variant site (in coxpd55); the 'disordered' region; an α-helix

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

Disease context

combined oxidative phosphorylation deficiency 55 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

POLRMT p.Gln681Ter Pathogenic/Likely pathogenic ★★ same condition
POLRMT p.Ala409Val Uncertain significance ★★ ⚠ same condition
POLRMT p.Ala444Val Uncertain significance ★★ ⚠ same condition
POLRMT p.Arg447Gln Uncertain significance ★★ ⚠ same condition
POLRMT p.Gly711Arg Uncertain significance ★★ ⚠ same condition
POLRMT p.Lys1109Arg Uncertain significance ★★ ⚠ same condition
POLRMT p.Lys169Arg Uncertain significance ★★ ⚠ same condition
POLRMT p.Lys201Glu Uncertain significance ★★ ⚠ same condition

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-pro741arg (accessed [today's date]).

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