Is PRRC2A p.Pro260Ser (c.778C>T) pathogenic?

PRRC2A p.Pro260Ser (c.778C>T) is classified Uncertain significance in PRRC2A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-07). AlphaMissense: likely pathogenic (0.6883); Ultra-rare (popmax 0.0166%, mid).

How common is PRRC2A p.Pro260Ser (c.778C>T) in the general population?

PRRC2A p.Pro260Ser (c.778C>T) is ultra-rare (popmax 0.0166%, mid) (gnomAD).

What do computational predictors say about PRRC2A p.Pro260Ser (c.778C>T)?

AlphaMissense predicts likely pathogenic (score 0.6883) — an in-silico prediction, not a clinical call.

PRRC2A p.Pro260Ser

c.778C>T · VCV4572647

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6883 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0166%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6883	likely pathogenic
REVEL	0.164	moderately benign-leaning
SaProt	LLR -8.36	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.4, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 1,808 bp · p 0.48 · regional, not allelic
Overall
CADD	23.5	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 0.0166% Middle Eastern · 1/6,042 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000379% 6/1,583,300 alleles · ultra-rare exomes 5/1,431,168 · genomes 1/152,132 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0166%	6,042
Admixed American	0.00334%	29,979
Remaining individualsnot grpmax-eligible	0.00163%	61,518
European (non-Finnish)	0.000173%	576,459

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.Pro260Ser
Coding: c.778C>T
MANE Select: NM_004638
Type: single nucleotide variant
Location: chr6:31625810 (GRCh38)
Gene constraint: LOEUF 0.322 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 40.07
Residue 260: the '4 x 57 aa type a repeats' region; 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-pro260ser (accessed [today's date]).

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