Is NRAP p.His100= (c.300C>T) pathogenic?

NRAP p.His100= (c.300C>T) is classified Benign in NRAP (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-04-09). Common (popmax 92.3%, amr) — too common for a highly-penetrant pathogenic allele.

NRAP p.His100=

Q: How common is NRAP p.His100= (c.300C>T) in the general population?

NRAP p.His100= (c.300C>T) is common (popmax 92.3%, amr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.300C>T · rs1891762 · VCV1258260

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Common

common (popmax 92.3%, amr) — too common for a highly-penetrant pathogenic allele

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.1	GERP -4.1
Overall
CADD	0.389	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 92.3% Admixed American · 55,340/59,986 alleles

Filtering AF 91.6% ClinGen BA1/BS1 input FAF95, joint · FAF99 91.3%

Overall 89.3% 1,433,129/1,605,634 alleles · common exomes 1,299,724/1,453,416 · genomes 133,405/152,218 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	93.1%	1
Admixed Americangrpmax	92.3%	1
Amishnot grpmax-eligible	91.6%	1
South Asian	89.7%	1
East Asian	89.6%	1
European (non-Finnish)	89.5%	1
Remaining individualsnot grpmax-eligible	88.3%	1
Middle Eastern	86.4%	1
Ashkenazi Jewishnot grpmax-eligible	84%	1
African / African-American	82.3%	1

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: NRAP
Protein: p.His100=
Coding: c.300C>T
MANE Select: NM_198060
dbSNP: rs1891762
Type: single nucleotide variant
Location: chr10:113657530 (GRCh38)
Gene constraint: LOEUF 1.045 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 51.98

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

Similar variants

NRAP p.His100Arg Uncertain significance ★ ⚠ same residue
NRAP p.Arg1037Ter Pathogenic/Likely pathogenic ★★ same type
NRAP p.Trp1033Ter Pathogenic/Likely pathogenic ★★ same type
NRAP c.360+1G>A Uncertain significance ★★ same type
NRAP p.Ala29Gly Uncertain significance ★★ ⚠ same type
NRAP p.Ala571Thr Uncertain significance ★★ same type
NRAP p.Arg1330Gln Uncertain significance ★★ ⚠ same type
NRAP p.Arg1559Gln Uncertain significance ★★ ⚠ same type

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/nrap-p-his100 (accessed [today's date]).

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