Is PARN p.Arg554Cys (c.1660C>T) pathogenic?

PARN p.Arg554Cys (c.1660C>T) is classified Uncertain significance in PARN (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-12-31). AlphaMissense: likely benign (0.0674); Ultra-rare (popmax 0.0135%, sas); Associated with Inborn genetic diseases.

How common is PARN p.Arg554Cys (c.1660C>T) in the general population?

PARN p.Arg554Cys (c.1660C>T) is ultra-rare (popmax 0.0135%, sas) (gnomAD).

What do computational predictors say about PARN p.Arg554Cys (c.1660C>T)?

AlphaMissense predicts likely benign (score 0.0674) — an in-silico prediction, not a clinical call.

PARN p.Arg554Cys

Q: What condition is associated with PARN p.Arg554Cys (c.1660C>T)?

PARN p.Arg554Cys (c.1660C>T) is associated with Inborn genetic diseases, dyskeratosis congenita, autosomal recessive 6, pulmonary fibrosis and/or bone marrow failure, Telomere-related, 4 (ClinVar).

c.1660C>T · rs754540436 · VCV1351322

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0674 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0135%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0674	likely benign
REVEL	0.006	strongly benign-leaning
SaProt	LLR -7.59	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.61	GERP -4, phastCons 0.031
Regional constraint	o/e 1.03	unconstrained · MANE · 193 kb · p 0.44 · regional, not allelic
Overall
CADD	12.22	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0135% South Asian · 12/88,590 alleles

Filtering AF 0.0078% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00608%

Overall 0.00225% 36/1,603,190 alleles · ultra-rare exomes 28/1,450,966 · genomes 8/152,224 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0135%	7,383
African / African-American	0.00807%	12,384
Remaining individualsnot grpmax-eligible	0.00322%	31,050
European (non-Finnish)	0.00136%	73,501

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.Arg554Cys
Coding: c.1660C>T
MANE Select: NM_002582
dbSNP: rs754540436
Type: single nucleotide variant
Location: chr16:14482648 (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

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.Arg554His Uncertain significance ★ ⚠ same residue
PARN p.Arg554Leu 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

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-arg554cys (accessed [today's date]).

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