Is PRORP p.Arg421Cys (c.1261C>T) pathogenic?

PRORP p.Arg421Cys (c.1261C>T) is classified Uncertain significance in PRORP (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-06-29). AlphaMissense: likely benign (0.2336); Ultra-rare (popmax 0.0368%, amr); Associated with combined oxidative phosphorylation deficiency 54.

What condition is associated with PRORP p.Arg421Cys (c.1261C>T)?

PRORP p.Arg421Cys (c.1261C>T) is associated with combined oxidative phosphorylation deficiency 54 (ClinVar).

How common is PRORP p.Arg421Cys (c.1261C>T) in the general population?

PRORP p.Arg421Cys (c.1261C>T) is ultra-rare (popmax 0.0368%, amr) (gnomAD).

What do computational predictors say about PRORP p.Arg421Cys (c.1261C>T)?

AlphaMissense predicts likely benign (score 0.2336) — an in-silico prediction, not a clinical call.

PRORP p.Arg421Cys

c.1261C>T · rs147065101 · VCV1292049

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2336 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0368%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

combined oxidative phosphorylation deficiency 54

Computational evidence

Protein change
AlphaMissense	0.2336	likely benign
REVEL	0.265	benign-leaning
SaProt	LLR -9.89	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 4.1	GERP 1.4, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 150 kb · p 0.092 · regional, not allelic
Overall
CADD	25.8	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 0.0368% Admixed American · 22/59,840 alleles

Filtering AF 0.0249% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0209%

Overall 0.0114% 183/1,600,534 alleles · ultra-rare exomes 167/1,448,428 · genomes 16/152,106 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0368%	2,720
Remaining individualsnot grpmax-eligible	0.021%	4,770
European (non-Finnish)	0.0126%	7,950
African / African-American	0.00134%	74,668

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.Arg421Cys
Coding: c.1261C>T
MANE Select: NM_014672
dbSNP: rs147065101
Type: single nucleotide variant
Location: chr14:35180763 (GRCh38)
Gene constraint: LOEUF 0.999 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.19 · 5 PDB
Residue 421: a UniProt-annotated variant site (in coxpd54; uncertain significance); the prorp domain

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

Similar variants

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.Arg445Gln Pathogenic/Likely pathogenic same condition
PRORP p.His504Tyr Likely pathogenic same condition
PRORP p.Ser298Ter 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-arg421cys (accessed [today's date]).

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