Is PRRC2A p.Pro1963Arg (c.5888C>G) pathogenic?

PRRC2A p.Pro1963Arg (c.5888C>G) is classified Uncertain significance in PRRC2A (ClinVar, Single submitter, 2 submitters; last evaluated 2025-08-15). AlphaMissense: likely benign (0.2549); Rare (popmax 0.691%, amr).

How common is PRRC2A p.Pro1963Arg (c.5888C>G) in the general population?

PRRC2A p.Pro1963Arg (c.5888C>G) is rare (popmax 0.691%, amr) (gnomAD).

What do computational predictors say about PRRC2A p.Pro1963Arg (c.5888C>G)?

AlphaMissense predicts likely benign (score 0.2549) — an in-silico prediction, not a clinical call.

PRRC2A p.Pro1963Arg

c.5888C>G · rs139221400 · VCV3034332

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2549 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.691%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2549	likely benign
REVEL	0.208	benign-leaning
SaProt	LLR -7.23	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 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 2,739 bp · p 0.034 · regional, not allelic
Overall
CADD	24.6	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 0.691% Admixed American · 409/59,218 alleles

Filtering AF 0.635% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.614%

Overall 0.0261% 420/1,608,508 alleles · rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.691%	145
Remaining individualsnot grpmax-eligible	0.0145%	6,915
East Asian	0.00223%	44,866
European (non-Finnish)	8.49e-05%	1,178,052

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: PRRC2A
Protein: p.Pro1963Arg
Coding: c.5888C>G
MANE Select: NM_004638
dbSNP: rs139221400
Type: single nucleotide variant
Location: chr6:31636562 (GRCh38)
Gene constraint: LOEUF 0.322 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 40.07
Residue 1963: the '3 x 50 aa type c repeats' region

Full PRRC2A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PRRC2A p.Ala1006Val Uncertain significance ★ ⚠ same type
PRRC2A p.Ala1268Thr Uncertain significance ★ ⚠ same type
PRRC2A p.Ala1302Pro Uncertain significance ★ ⚠ same type
PRRC2A p.Ala1361Gly Uncertain significance ★ ⚠ same type
PRRC2A p.Ala1405Pro Uncertain significance ★ ⚠ same type
PRRC2A p.Ala1405Val Uncertain significance ★ ⚠ same type
PRRC2A p.Ala145Thr Uncertain significance ★ ⚠ same type
PRRC2A p.Ala1474Thr 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/prrc2a-p-pro1963arg (accessed [today's date]).

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