Is PARN p.Tyr91Cys (c.272A>G) pathogenic?

PARN p.Tyr91Cys (c.272A>G) is classified Conflicting classifications of pathogenicity in PARN (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2025-12-17). AlphaMissense: likely pathogenic (0.5669); Ultra-rare (popmax 0.0134%, amr); Associated with PARN-related disorder.

How common is PARN p.Tyr91Cys (c.272A>G) in the general population?

PARN p.Tyr91Cys (c.272A>G) is ultra-rare (popmax 0.0134%, amr) (gnomAD).

What do computational predictors say about PARN p.Tyr91Cys (c.272A>G)?

AlphaMissense predicts likely pathogenic (score 0.5669) — an in-silico prediction, not a clinical call.

PARN p.Tyr91Cys

Q: What condition is associated with PARN p.Tyr91Cys (c.272A>G)?

PARN p.Tyr91Cys (c.272A>G) is associated with PARN-related disorder, dyskeratosis congenita, autosomal recessive 6, pulmonary fibrosis and/or bone marrow failure, Telomere-related, 4 (ClinVar).

c.272A>G · rs201765587 · VCV542669

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

AlphaMissense

likely pathogenic

0.5669 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0134%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

PARN-related disorder

Computational evidence

Protein change
AlphaMissense	0.5669	likely pathogenic
REVEL	0.578	indeterminate
SaProt	LLR -12.20	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>A here scores Δ0.25 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.9	phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 193 kb · p 0.44 · regional, not allelic
Overall
CADD	32.0	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

Grpmax group 0.0134% Admixed American · 8/59,576 alleles

Filtering AF 0.00666% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00485%

Overall 0.00548% 88/1,605,790 alleles · ultra-rare exomes 74/1,453,486 · genomes 14/152,304 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0134%	7,447
East Asian	0.0112%	8,963
African / African-American	0.00667%	14,986
European (non-Finnish)	0.00537%	18,630
Remaining individualsnot grpmax-eligible	0.00482%	20,744
South Asian	0.00333%	30,059
Finnishnot grpmax-eligible	0.00156%	63,932

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.Tyr91Cys
Coding: c.272A>G
MANE Select: NM_002582
dbSNP: rs201765587
Type: single nucleotide variant
Location: chr16:14627161 (GRCh38)
Gene constraint: LOEUF 0.918 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 81.60 · 3 PDB
Residue 91: a β-strand

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

Disease context

PARN-related disorder

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

Similar variants

PARN p.Tyr91Asn Uncertain significance ★ ⚠ same residue
PARN p.Tyr91Phe 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-tyr91cys (accessed [today's date]).

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