Is PRRC2A p.Pro559Ser (c.1675C>T) pathogenic?

PRRC2A p.Pro559Ser (c.1675C>T) is classified Benign in PRRC2A (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-05-02). AlphaMissense: likely benign (0.0861); Low-frequency (popmax 1.34%, mid); Associated with PRRC2A-related disorder.

What condition is associated with PRRC2A p.Pro559Ser (c.1675C>T)?

PRRC2A p.Pro559Ser (c.1675C>T) is associated with PRRC2A-related disorder (ClinVar).

How common is PRRC2A p.Pro559Ser (c.1675C>T) in the general population?

PRRC2A p.Pro559Ser (c.1675C>T) is low-frequency (popmax 1.34%, mid) (gnomAD).

What do computational predictors say about PRRC2A p.Pro559Ser (c.1675C>T)?

AlphaMissense predicts likely benign (score 0.0861) — an in-silico prediction, not a clinical call.

PRRC2A p.Pro559Ser

c.1675C>T · rs45544132 · VCV3037429

Benign No assertion criteria

Classification

Benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0861 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.34%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

PRRC2A-related disorder

Computational evidence

Protein change
AlphaMissense	0.0861	likely benign
REVEL	0.107	moderately benign-leaning
SaProt	LLR -7.05	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 2.7	GERP 1.6, phastCons 0.99
Regional constraint	o/e 1.13	unconstrained · MANE · 7,920 bp · p 1.9e-08 · regional, not allelic
Overall
CADD	15.85	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 1.34% Middle Eastern · 81/6,060 alleles

Filtering AF 1.1% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.02%

Overall 0.255% 4,119/1,613,032 alleles · low-frequency exomes 3,826/1,460,720 · genomes 293/152,312 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	1.34%	75
Ashkenazi Jewishnot grpmax-eligible	0.682%	147
Remaining individualsnot grpmax-eligible	0.349%	287
Admixed American	0.342%	293
European (non-Finnish)	0.283%	354
African / African-American	0.0613%	1,632
South Asian	0.0242%	4,140
Finnishnot grpmax-eligible	0.0111%	8,996
East Asian	0.00223%	44,882

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.Pro559Ser
Coding: c.1675C>T
MANE Select: NM_004638
dbSNP: rs45544132
Type: single nucleotide variant
Location: chr6:31628149 (GRCh38)
Gene constraint: LOEUF 0.322 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 40.07
Residue 559: 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

Disease context

PRRC2A-related disorder

Similar variants

PRRC2A p.Lys308Arg Uncertain significance ⚠ same condition
PRRC2A c.391-6C>A Likely benign same condition
PRRC2A c.4720-6C>G Likely benign same condition
PRRC2A c.5624+9C>T Benign same condition
PRRC2A c.760-10C>G Likely benign same condition
PRRC2A c.*9C>T Likely benign same condition
PRRC2A p.Ala1222= Likely benign same condition
PRRC2A p.Ala1283Thr Benign 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/prrc2a-p-pro559ser (accessed [today's date]).

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