Is PCNA p.Leu221= (c.663C>G) pathogenic?

PCNA p.Leu221= (c.663C>G) is classified Likely benign in PCNA (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-01). Very rare (popmax 0.00167%, amr).

How common is PCNA p.Leu221= (c.663C>G) in the general population?

PCNA p.Leu221= (c.663C>G) is very rare (popmax 0.00167%, amr) (gnomAD).

PCNA p.Leu221=

c.663C>G · VCV4535476

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -4.2	GERP -3.8
Overall
CADD	1.37	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/60,010 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000313%

Overall 0.000682% 11/1,613,838 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,010
European (non-Finnish)	0.000848%	117,981

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: PCNA
Protein: p.Leu221=
Coding: c.663C>G
MANE Select: NM_182649
Type: single nucleotide variant
Location: chr20:5115492 (GRCh38)
Gene constraint: LOEUF 0.42 · pLI 0.99 (gnomAD)
Structure: AlphaFold pLDDT 94.38 · 103 PDB
Residue 221: an α-helix

Full PCNA gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PCNA p.Cys148Ser Likely pathogenic ★★ same type
PCNA p.Ser228Ile Uncertain significance ★★ ⚠ same type
PCNA p.Ala242= Benign/Likely benign ★★ same type
PCNA p.Pro234= Benign ★★ same type
PCNA p.Arg53Gln Uncertain significance ★ ⚠ same type
PCNA p.Asn24Ser Uncertain significance ★ ⚠ same type
PCNA p.Gly56Ser Uncertain significance ★ ⚠ same type
PCNA p.Leu182Phe 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/pcna-p-leu221 (accessed [today's date]).

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