Is PARN p.Leu159= (c.475C>T) pathogenic?

PARN p.Leu159= (c.475C>T) is classified Likely benign in PARN (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-11). Very rare (popmax 0.000427%, nfe); Associated with pulmonary fibrosis and/or bone marrow failure, Telomere-related, 4.

How common is PARN p.Leu159= (c.475C>T) in the general population?

PARN p.Leu159= (c.475C>T) is very rare (popmax 0.000427%, nfe) (gnomAD).

PARN p.Leu159=

Q: What condition is associated with PARN p.Leu159= (c.475C>T)?

PARN p.Leu159= (c.475C>T) is associated with pulmonary fibrosis and/or bone marrow failure, Telomere-related, 4, dyskeratosis congenita, autosomal recessive 6 (ClinVar).

c.475C>T · VCV4788460

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000427%, nfe)

Conditions

pulmonary fibrosis and/or bone marrow failure, Telomere-related, 4

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 2.1	GERP 1.1, phastCons 1
Overall
CADD	6.192	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000427% European (non-Finnish) · 5/1,171,114 alleles

Filtering AF 0.000125% ClinGen BA1/BS1 input FAF95, joint · FAF99 9.1e-05%

Overall 0.000312% 5/1,604,224 alleles · very rare exomes 4/1,452,058 · genomes 1/152,166 · joint denominator

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: PARN
Protein: p.Leu159=
Coding: c.475C>T
MANE Select: NM_002582
Type: single nucleotide variant
Location: chr16:14610723 (GRCh38)
Gene constraint: LOEUF 0.918 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 81.60 · 3 PDB

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

Disease context

pulmonary fibrosis and/or bone marrow failure, Telomere-related, 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: dyskeratosis congenita, autosomal recessive 6

Similar variants

PARN c.1006-2A>G Pathogenic/Likely pathogenic ★★ same condition
PARN c.1405+1G>T Likely pathogenic ★★ same condition
PARN c.1481-1G>A Pathogenic/Likely pathogenic ★★ same condition
PARN c.178-1G>C Likely pathogenic ★★ same condition
PARN c.784-1G>A Likely pathogenic ★★ same condition
PARN c.962+2T>C Pathogenic/Likely pathogenic ★★ same condition
PARN p.Arg128Ter Pathogenic/Likely pathogenic ★★ same condition
PARN p.Arg237Ter Pathogenic/Likely pathogenic ★★ same condition

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/parn-p-leu159 (accessed [today's date]).

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