Is PRRC2A p.Phe2083Ser (c.6248T>C) pathogenic?

PRRC2A p.Phe2083Ser (c.6248T>C) is classified Benign in PRRC2A (ClinVar, Single submitter, 2 submitters; last evaluated 2025-07-01). AlphaMissense: ambiguous (0.3806); Common (popmax 9.7%, mid) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about PRRC2A p.Phe2083Ser (c.6248T>C)?

AlphaMissense predicts ambiguous (score 0.3806) — an in-silico prediction, not a clinical call.

PRRC2A p.Phe2083Ser

Q: How common is PRRC2A p.Phe2083Ser (c.6248T>C) in the general population?

PRRC2A p.Phe2083Ser (c.6248T>C) is common (popmax 9.7%, mid) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.6248T>C · rs35595439 · VCV3055548

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3806 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 9.7%, mid) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3806	ambiguous
REVEL	0.107	moderately benign-leaning
SaProt	LLR -4.62	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 6.1	GERP 1.7, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 2,739 bp · p 0.034 · regional, not allelic
Overall
CADD	23.5	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 9.7% Middle Eastern · 588/6,062 alleles

Filtering AF 9.05% ClinGen BA1/BS1 input FAF95, joint · FAF99 8.79%

Overall 0.979% 15,773/1,611,058 alleles · common

Ancestry group	Frequency	1 in
Middle Easterngrpmax	9.7%	10
South Asian	2.41%	41
Ashkenazi Jewishnot grpmax-eligible	2.41%	42
Remaining individualsnot grpmax-eligible	1.38%	73
Admixed American	1.05%	96
European (non-Finnish)	0.867%	115
African / African-American	0.638%	157
East Asian	0.109%	916
Finnishnot grpmax-eligible	0.0842%	1,187

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.Phe2083Ser
Coding: c.6248T>C
MANE Select: NM_004638
dbSNP: rs35595439
Type: single nucleotide variant
Location: chr6:31637239 (GRCh38)
Gene constraint: LOEUF 0.322 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 40.07
Residue 2083: the '3 x 50 aa type c 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-phe2083ser (accessed [today's date]).

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