Is PRRC2A p.Pro500Ser (c.1498C>T) pathogenic?

PRRC2A p.Pro500Ser (c.1498C>T) is classified Uncertain significance in PRRC2A (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-27). AlphaMissense: likely benign (0.2188); Very rare (popmax 0.00988%, sas).

How common is PRRC2A p.Pro500Ser (c.1498C>T) in the general population?

PRRC2A p.Pro500Ser (c.1498C>T) is very rare (popmax 0.00988%, sas) (gnomAD).

What do computational predictors say about PRRC2A p.Pro500Ser (c.1498C>T)?

AlphaMissense predicts likely benign (score 0.2188) — an in-silico prediction, not a clinical call.

PRRC2A p.Pro500Ser

c.1498C>T · rs146082098 · VCV2336727

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2188 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00988%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2188	likely benign
REVEL	0.054	moderately benign-leaning
SaProt	LLR -6.26	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 7.6	GERP 0.58, phastCons 1
Regional constraint	o/e 1.13	unconstrained · MANE · 7,920 bp · p 1.9e-08 · regional, not allelic
Overall
CADD	23.4	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 0.00988% South Asian · 9/91,090 alleles

Filtering AF 0.00514% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00375%

Overall 0.00254% 41/1,612,892 alleles · very rare exomes 37/1,460,694 · genomes 4/152,198 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00988%	10,121
Remaining individualsnot grpmax-eligible	0.0032%	31,238
European (non-Finnish)	0.00254%	39,334

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.Pro500Ser
Coding: c.1498C>T
MANE Select: NM_004638
dbSNP: rs146082098
Type: single nucleotide variant
Location: chr6:31627972 (GRCh38)
Gene constraint: LOEUF 0.322 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 40.07
Residue 500: the '4 x 57 aa type a repeats' region; the 'disordered' region; the '2 x type b 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-pro500ser (accessed [today's date]).

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