Is PARN p.Arg99Lys (c.296G>A) pathogenic?

PARN p.Arg99Lys (c.296G>A) is classified Uncertain significance in PARN (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-12). AlphaMissense: ambiguous (0.4685); Absent from gnomAD v4.1; Associated with pulmonary fibrosis and/or bone marrow failure, Telomere-related, 4.

How common is PARN p.Arg99Lys (c.296G>A) in the general population?

PARN p.Arg99Lys (c.296G>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PARN p.Arg99Lys (c.296G>A)?

AlphaMissense predicts ambiguous (score 0.4685) — an in-silico prediction, not a clinical call.

PARN p.Arg99Lys

Q: What condition is associated with PARN p.Arg99Lys (c.296G>A)?

PARN p.Arg99Lys (c.296G>A) is associated with pulmonary fibrosis and/or bone marrow failure, Telomere-related, 4, dyskeratosis congenita, autosomal recessive 6 (ClinVar).

c.296G>A · VCV4784957

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4685 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

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

Computational evidence

Protein change
AlphaMissense	0.4685	ambiguous
REVEL	0.113	moderately benign-leaning
SaProt	LLR -6.24	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	Δ0.55	acceptor loss, 1 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 7.7	phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 193 kb · p 0.44 · 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: PARN
Protein: p.Arg99Lys
Coding: c.296G>A
MANE Select: NM_002582
Type: single nucleotide variant
Location: chr16:14627137 (GRCh38)
Gene constraint: LOEUF 0.918 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 81.60 · 3 PDB
Residue 99: a β-strand

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 p.Arg99Thr 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-arg99lys (accessed [today's date]).

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