Is PARN p.Ser280= (c.840G>A) pathogenic?

PARN p.Ser280= (c.840G>A) is classified Uncertain significance in PARN (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-26). Very rare (popmax 0.00445%, nfe); Associated with Inborn genetic diseases.

How common is PARN p.Ser280= (c.840G>A) in the general population?

PARN p.Ser280= (c.840G>A) is very rare (popmax 0.00445%, nfe) (gnomAD).

PARN p.Ser280=

Q: What condition is associated with PARN p.Ser280= (c.840G>A)?

PARN p.Ser280= (c.840G>A) is associated with Inborn genetic diseases, dyskeratosis congenita, autosomal recessive 6, pulmonary fibrosis and/or bone marrow failure, Telomere-related, 4 (ClinVar).

c.840G>A · rs200026431 · VCV1423263

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00445%, nfe)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.47	donor loss · deltas
Pangolin	Δ0.67	gain · loss 0.54 · SpliceAI calls loss · independent
Constraint at this position
Conservation	phyloP -0.73	GERP -4.6, phastCons 0.006
Overall
CADD	21.0	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00445% European (non-Finnish) · 52/1,168,696 alleles

Filtering AF 0.00345% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00313%

Overall 0.00357% 57/1,595,394 alleles · very rare exomes 51/1,443,356 · genomes 6/152,038 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00445%	22,475
South Asian	0.0034%	29,435
East Asian	0.00225%	44,492
Remaining individualsnot grpmax-eligible	0.00162%	61,756

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.Ser280=
Coding: c.840G>A
MANE Select: NM_002582
dbSNP: rs200026431
Type: single nucleotide variant
Location: chr16:14599904 (GRCh38)
Gene constraint: LOEUF 0.918 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 81.60 · 3 PDB
Residue 280: an α-helix

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: dyskeratosis congenita, autosomal recessive 6 pulmonary fibrosis and/or bone marrow failure, Telomere-related, 4

Similar variants

PARN p.Ser280Leu Uncertain significance ★★ ⚠ same residue
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

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-ser280 (accessed [today's date]).

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