Is NRAP p.Pro1360Ser (c.4078C>T) pathogenic?

NRAP p.Pro1360Ser (c.4078C>T) is classified Uncertain significance in NRAP (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-02). AlphaMissense: ambiguous (0.3611); Very rare (popmax 0.00133%, afr); Associated with NRAP-related disorder.

What condition is associated with NRAP p.Pro1360Ser (c.4078C>T)?

NRAP p.Pro1360Ser (c.4078C>T) is associated with NRAP-related disorder (ClinVar).

How common is NRAP p.Pro1360Ser (c.4078C>T) in the general population?

NRAP p.Pro1360Ser (c.4078C>T) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about NRAP p.Pro1360Ser (c.4078C>T)?

AlphaMissense predicts ambiguous (score 0.3611) — an in-silico prediction, not a clinical call.

NRAP p.Pro1360Ser

c.4078C>T · rs749650466 · VCV2631465

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3611 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

NRAP-related disorder

Computational evidence

Protein change
AlphaMissense	0.3611	ambiguous
REVEL	0.252	benign-leaning
SaProt	LLR -6.99	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.6	GERP -0.28, phastCons 1
Overall
CADD	21.8	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 0.00133% African / African-American · 1/74,938 alleles

Overall 6.2e-05% 1/1,614,066 alleles · very rare exomes 0/1,461,860 · genomes 1/152,206 · 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: NRAP
Protein: p.Pro1360Ser
Coding: c.4078C>T
MANE Select: NM_198060
dbSNP: rs749650466
Type: single nucleotide variant
Location: chr10:113604758 (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

Disease context

NRAP-related disorder

Similar variants

NRAP p.Arg1037Ter Pathogenic/Likely pathogenic ★★ same condition
NRAP p.Trp1033Ter Pathogenic/Likely pathogenic ★★ same condition
NRAP c.1843-2A>G Likely pathogenic ★ same condition
NRAP p.Gln24His Pathogenic ★ same condition
NRAP p.Gln607Ter Likely pathogenic ★ same condition
NRAP p.Glu1256Ter Likely pathogenic ★ same condition
NRAP p.Tyr127Ter Likely pathogenic ★ same condition
NRAP p.Tyr448Ter 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/nrap-p-pro1360ser (accessed [today's date]).

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