Is PCNA p.Cys148Ser (c.443G>C) pathogenic?

PCNA p.Cys148Ser (c.443G>C) is classified Likely pathogenic in PCNA (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-18). AlphaMissense: likely pathogenic (0.9214); Very rare (popmax 0.00167%, amr); Associated with ataxia-telangiectasia-like disorder 2.

What condition is associated with PCNA p.Cys148Ser (c.443G>C)?

PCNA p.Cys148Ser (c.443G>C) is associated with ataxia-telangiectasia-like disorder 2 (ClinVar).

How common is PCNA p.Cys148Ser (c.443G>C) in the general population?

PCNA p.Cys148Ser (c.443G>C) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about PCNA p.Cys148Ser (c.443G>C)?

AlphaMissense predicts likely pathogenic (score 0.9214) — an in-silico prediction, not a clinical call.

PCNA p.Cys148Ser

Q: How is PCNA-related progressive neurodegenerative photosensitivity syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.443G>C · rs1274412848 · VCV803596

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9214 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ataxia-telangiectasia-like disorder 2

Computational evidence

Protein change
AlphaMissense	0.9214	likely pathogenic ✓ concordant with ClinVar
REVEL	0.913	moderately pathogenic-leaning
SaProt	LLR -11.07	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 6	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

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/59,988 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000274% 4/1,461,566 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,988
European (non-Finnish)	0.000254%	393,283

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.Cys148Ser
Coding: c.443G>C
MANE Select: NM_182649
dbSNP: rs1274412848
Type: single nucleotide variant
Location: chr20:5117609 (GRCh38)
Gene constraint: LOEUF 0.42 · pLI 0.99 (gnomAD)
Structure: AlphaFold pLDDT 94.38 · 103 PDB
Residue 148: an α-helix; a disulfide bond

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

Disease context

ataxia-telangiectasia-like disorder 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For PCNA-related progressive neurodegenerative photosensitivity syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

PCNA p.Ser228Ile Uncertain significance ★★ ⚠ same condition
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
PCNA p.Leu182Trp 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-cys148ser (accessed [today's date]).

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