Is PRORP p.Arg445Gln (c.1334G>A) pathogenic?

PRORP p.Arg445Gln (c.1334G>A) is classified Pathogenic/Likely pathogenic in PRORP (ClinVar, No assertion criteria, 3 submitters; last evaluated 2024-03-11). AlphaMissense: likely pathogenic (0.5975); Very rare (popmax 0.00534%, afr); Associated with combined oxidative phosphorylation deficiency 54.

What condition is associated with PRORP p.Arg445Gln (c.1334G>A)?

PRORP p.Arg445Gln (c.1334G>A) is associated with combined oxidative phosphorylation deficiency 54, microcephaly, lactic acidosis (ClinVar).

How common is PRORP p.Arg445Gln (c.1334G>A) in the general population?

PRORP p.Arg445Gln (c.1334G>A) is very rare (popmax 0.00534%, afr) (gnomAD).

What do computational predictors say about PRORP p.Arg445Gln (c.1334G>A)?

AlphaMissense predicts likely pathogenic (score 0.5975) — an in-silico prediction, not a clinical call.

PRORP p.Arg445Gln

c.1334G>A · rs777185638 · VCV638209

Pathogenic/Likely pathogenic No assertion criteria

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.5975 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00534%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

combined oxidative phosphorylation deficiency 54

Computational evidence

Protein change
AlphaMissense	0.5975	likely pathogenic ✓ concordant with ClinVar
REVEL	0.495	indeterminate
SaProt	LLR -11.09	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.6	GERP 0.77, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 150 kb · p 0.092 · regional, not allelic
Overall
CADD	32.0	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 0.00534% African / African-American · 4/74,906 alleles

Filtering AF 0.00283% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00252%

Overall 0.00322% 52/1,614,002 alleles · very rare exomes 46/1,461,868 · genomes 6/152,134 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00534%	18,726
European (non-Finnish)	0.00373%	26,819
Finnishnot grpmax-eligible	0.00312%	32,009
Remaining individualsnot grpmax-eligible	0.0016%	62,486
South Asian	0.0011%	91,086

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: PRORP
Protein: p.Arg445Gln
Coding: c.1334G>A
MANE Select: NM_014672
dbSNP: rs777185638
Type: single nucleotide variant
Location: chr14:35266785 (GRCh38)
Gene constraint: LOEUF 0.999 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.19 · 5 PDB
Residue 445: a UniProt-annotated variant site (in coxpd54; results in decreased mitochondrial trna 5'-end processing as shown by assays with mitochondrial ribonuclease p complex reconstituted in vitro); the prorp domain; a β-strand

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

Disease context

combined oxidative phosphorylation deficiency 54 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: microcephaly lactic acidosis

Similar variants

PRORP p.Arg445Trp Uncertain significance ★ ⚠ same residue
PRORP p.Arg421Cys Uncertain significance ★★ ⚠ same condition
PRORP p.Arg502Gln Uncertain significance ★★ ⚠ same condition
PRORP p.Asn412Ser Uncertain significance ★★ ⚠ same condition
PRORP p.Ala434Asp Likely pathogenic ★ ⚠ same condition
PRORP p.Gln312Ter Uncertain significance ★ same condition
PRORP p.Ala485Val Pathogenic/Likely pathogenic ⚠ same condition
PRORP p.His504Tyr Likely pathogenic 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/prorp-p-arg445gln (accessed [today's date]).

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