Is PCNA p.Ser42Leu (c.125C>T) pathogenic?

PCNA p.Ser42Leu (c.125C>T) is classified Uncertain significance in PCNA (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-26). AlphaMissense: likely pathogenic (0.5921); Ultra-rare (popmax 0.0117%, amr).

How common is PCNA p.Ser42Leu (c.125C>T) in the general population?

PCNA p.Ser42Leu (c.125C>T) is ultra-rare (popmax 0.0117%, amr) (gnomAD).

What do computational predictors say about PCNA p.Ser42Leu (c.125C>T)?

AlphaMissense predicts likely pathogenic (score 0.5921) — an in-silico prediction, not a clinical call.

PCNA p.Ser42Leu

c.125C>T · VCV3305196

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5921 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0117%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.5921	likely pathogenic
REVEL	0.855	moderately pathogenic-leaning
SaProt	LLR -12.88	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.50	unconstrained · MANE · 4,512 bp · p 2.9e-19 · regional, not allelic
Overall
CADD	31.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0117% Admixed American · 7/59,822 alleles

Filtering AF 0.00545% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00381%

Overall 0.000806% 13/1,612,540 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0117%	8,546
Remaining individualsnot grpmax-eligible	0.00801%	12,484
East Asian	0.00223%	44,812

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.Ser42Leu
Coding: c.125C>T
MANE Select: NM_182649
Type: single nucleotide variant
Location: chr20:5119674 (GRCh38)
Gene constraint: LOEUF 0.42 · pLI 0.99 (gnomAD)
Structure: AlphaFold pLDDT 94.38 · 103 PDB
Residue 42: the 'interaction with nudt15' region

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-ser42leu (accessed [today's date]).

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