Is NHP2 p.Pro33Ser (c.97C>T) pathogenic?

NHP2 p.Pro33Ser (c.97C>T) is classified Uncertain significance in NHP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-06). AlphaMissense: likely benign (0.2593); Very rare (popmax 0.00446%, eas); Associated with dyskeratosis congenita.

What condition is associated with NHP2 p.Pro33Ser (c.97C>T)?

NHP2 p.Pro33Ser (c.97C>T) is associated with dyskeratosis congenita (ClinVar).

How common is NHP2 p.Pro33Ser (c.97C>T) in the general population?

NHP2 p.Pro33Ser (c.97C>T) is very rare (popmax 0.00446%, eas) (gnomAD).

How is Dyskeratosis congenita inherited?

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

What do computational predictors say about NHP2 p.Pro33Ser (c.97C>T)?

AlphaMissense predicts likely benign (score 0.2593) — an in-silico prediction, not a clinical call.

NHP2 p.Pro33Ser

c.97C>T · VCV3613116

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2593 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

dyskeratosis congenita

Computational evidence

Protein change
AlphaMissense	0.2593	likely benign
REVEL	0.116	moderately benign-leaning
SaProt	LLR -11.24	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.6	phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 4,101 bp · p 0.31 · regional, not allelic
Overall
CADD	23.1	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 0.00446% East Asian · 2/44,886 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.000124% 2/1,613,992 alleles · very rare exomes 1/1,461,620 · genomes 1/152,372 · joint denominator

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: NHP2
Protein: p.Pro33Ser
Coding: c.97C>T
MANE Select: NM_017838
Type: single nucleotide variant
Location: chr5:178153721 (GRCh38)
Gene constraint: LOEUF 1.123 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 80.73 · 7 PDB

Full NHP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

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

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

NHP2 p.Ala17Val Uncertain significance ★★ ⚠ same condition
NHP2 p.Ala39Thr Uncertain significance ★★ ⚠ same condition
NHP2 p.Arg101Gly Uncertain significance ★★ ⚠ same condition
NHP2 p.Arg61Gln Uncertain significance ★★ ⚠ same condition
NHP2 p.Asp9Asn Uncertain significance ★★ ⚠ same condition
NHP2 p.Glu12Gln Uncertain significance ★★ ⚠ same condition
NHP2 p.Glu145Val Uncertain significance ★★ ⚠ same condition
NHP2 p.Gly63Arg Uncertain significance ★★ ⚠ 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/nhp2-p-pro33ser (accessed [today's date]).

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