Is NHP2 p.Pro87Ser (c.259C>T) pathogenic?

NHP2 p.Pro87Ser (c.259C>T) is classified Uncertain significance in NHP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-22). AlphaMissense: likely pathogenic (0.9979); Very rare (popmax 0.00167%, amr); Associated with dyskeratosis congenita.

What condition is associated with NHP2 p.Pro87Ser (c.259C>T)?

NHP2 p.Pro87Ser (c.259C>T) is associated with dyskeratosis congenita (ClinVar).

How common is NHP2 p.Pro87Ser (c.259C>T) in the general population?

NHP2 p.Pro87Ser (c.259C>T) is very rare (popmax 0.00167%, amr) (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.Pro87Ser (c.259C>T)?

AlphaMissense predicts likely pathogenic (score 0.9979) — an in-silico prediction, not a clinical call.

NHP2 p.Pro87Ser

c.259C>T · rs370656580 · VCV2148557

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9979 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

dyskeratosis congenita

Computational evidence

Protein change
AlphaMissense	0.9979	likely pathogenic · top 2% in NHP2
REVEL	0.853	moderately pathogenic-leaning
SaProt	LLR -13.50	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 4,101 bp · p 0.31 · regional, not allelic
Overall
CADD	26.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00167% Admixed American · 1/60,012 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000496% 8/1,613,822 alleles · very rare exomes 8/1,461,536 · genomes 0/152,286 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,012
European (non-Finnish)	0.000593%	168,560

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.Pro87Ser
Coding: c.259C>T
MANE Select: NM_017838
dbSNP: rs370656580
Type: single nucleotide variant
Location: chr5:178150965 (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-pro87ser (accessed [today's date]).

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