Is PARN p.Phe419fs (c.1257del) pathogenic?

PARN p.Phe419fs (c.1257del) is classified Pathogenic in PARN (ClinVar, Single submitter, 2 submitters; last evaluated 2025-08-04). Very rare (popmax 0.00163%, nfe); Associated with dyskeratosis congenita, autosomal recessive 6.

What condition is associated with PARN p.Phe419fs (c.1257del)?

PARN p.Phe419fs (c.1257del) is associated with dyskeratosis congenita, autosomal recessive 6, pulmonary fibrosis, pulmonary fibrosis and/or bone marrow failure, Telomere-related, 4 (ClinVar).

How common is PARN p.Phe419fs (c.1257del) in the general population?

PARN p.Phe419fs (c.1257del) is very rare (popmax 0.00163%, nfe) (gnomAD).

How is Dyskeratosis congenita inherited?

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

PARN p.Phe419fs

c.1257del · rs942538351 · VCV834007

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00163%, nfe)

Conditions

dyskeratosis congenita, autosomal recessive 6

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 18 of 24
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.8	GERP 2.2, phastCons 1
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00163% European (non-Finnish) · 19/1,162,820 alleles

Filtering AF 0.00104% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000842%

Overall 0.00125% 20/1,594,652 alleles · very rare exomes 18/1,442,518 · genomes 2/152,134 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00163%	61,201
African / African-American	0.00134%	74,570

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.Phe419fs
Coding: c.1257del
MANE Select: NM_002582
dbSNP: rs942538351
Type: Deletion
Location: chr16:14580879 (GRCh38)
Gene constraint: LOEUF 0.918 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 81.60 · 3 PDB
Residue 419: a β-strand

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

Disease context

dyskeratosis congenita, autosomal recessive 6 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

For Dyskeratosis congenita (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked recessive
Onset: Adolescent, Adult, Childhood, Infancy, Neonatal
Prevalence: 1-9 / 1 000 000 (Europe)

Similar variants

PARN p.Phe419= Likely benign ★ same residue
PARN p.Val318fs Pathogenic ★★ same condition
PARN c.840+6del Benign/Likely benign ★★ same condition
PARN c.1263-11_1269del Likely pathogenic ★ same condition
PARN c.1319-2_1319del Likely pathogenic ★ same condition
PARN c.177+1del Pathogenic ★ same condition
PARN c.784-170_840+174del Likely pathogenic ★ same condition
PARN p.Arg237_Tyr238insTer 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-phe419fs (accessed [today's date]).

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