Is PRRC2A p.Arg2127Pro (c.6380G>C) pathogenic?

PRRC2A p.Arg2127Pro (c.6380G>C) is classified Uncertain significance in PRRC2A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-06). AlphaMissense: ambiguous (0.4187); Very rare (popmax 0.00736%, amr).

How common is PRRC2A p.Arg2127Pro (c.6380G>C) in the general population?

PRRC2A p.Arg2127Pro (c.6380G>C) is very rare (popmax 0.00736%, amr) (gnomAD).

What do computational predictors say about PRRC2A p.Arg2127Pro (c.6380G>C)?

AlphaMissense predicts ambiguous (score 0.4187) — an in-silico prediction, not a clinical call.

PRRC2A p.Arg2127Pro

c.6380G>C · VCV3938867

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4187 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00736%, amr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4187	ambiguous
REVEL	0.109	moderately benign-leaning
SaProt	LLR -5.44	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.7	GERP 1.7, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 2,739 bp · p 0.034 · regional, not allelic
Overall
CADD	23.2	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 0.00736% Admixed American · 4/54,376 alleles

Filtering AF 0.00242% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00146%

Overall 0.000318% 5/1,573,614 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00736%	13,594
Remaining individualsnot grpmax-eligible	0.00165%	60,600

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.Arg2127Pro
Coding: c.6380G>C
MANE Select: NM_004638
Type: single nucleotide variant
Location: chr6:31637492 (GRCh38)
Gene constraint: LOEUF 0.322 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 40.07
Residue 2127: the 'disordered' 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-arg2127pro (accessed [today's date]).

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