Is NHP2 p.Pro123= (c.369C>T) pathogenic?

NHP2 p.Pro123= (c.369C>T) is classified Benign/Likely benign in NHP2 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-01-26). Ultra-rare (popmax 0.0277%, nfe); Associated with dyskeratosis congenita.

What condition is associated with NHP2 p.Pro123= (c.369C>T)?

NHP2 p.Pro123= (c.369C>T) is associated with dyskeratosis congenita (ClinVar).

How common is NHP2 p.Pro123= (c.369C>T) in the general population?

NHP2 p.Pro123= (c.369C>T) is ultra-rare (popmax 0.0277%, nfe) (gnomAD).

How is Dyskeratosis congenita inherited?

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

NHP2 p.Pro123=

c.369C>T · rs375285426 · VCV435986

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0277%, nfe)

Conditions

dyskeratosis congenita

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.103	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.5	phastCons 1
Overall
CADD	9.022	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0277% European (non-Finnish) · 327/1,179,870 alleles

Filtering AF 0.0252% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0242%

Overall 0.0229% 369/1,613,772 alleles · ultra-rare exomes 317/1,461,578 · genomes 52/152,194 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0515%	1,940
European (non-Finnish)grpmax	0.0277%	3,608
Remaining individualsnot grpmax-eligible	0.0128%	7,808
African / African-American	0.00133%	74,922

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro123=
Coding: c.369C>T
MANE Select: NM_017838
dbSNP: rs375285426
Type: single nucleotide variant
Location: chr5:178149806 (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-pro123 (accessed [today's date]).

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