Is NRAP p.Thr668Pro (c.2002A>C) pathogenic?

NRAP p.Thr668Pro (c.2002A>C) is classified Uncertain significance in NRAP (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-25). AlphaMissense: ambiguous (0.4034); Very rare (popmax 0.0017%, nfe); Associated with Inborn genetic diseases.

What condition is associated with NRAP p.Thr668Pro (c.2002A>C)?

NRAP p.Thr668Pro (c.2002A>C) is associated with Inborn genetic diseases (ClinVar).

How common is NRAP p.Thr668Pro (c.2002A>C) in the general population?

NRAP p.Thr668Pro (c.2002A>C) is very rare (popmax 0.0017%, nfe) (gnomAD).

What do computational predictors say about NRAP p.Thr668Pro (c.2002A>C)?

AlphaMissense predicts ambiguous (score 0.4034) — an in-silico prediction, not a clinical call.

NRAP p.Thr668Pro

c.2002A>C · rs1218484255 · VCV2303624

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4034 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0017%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4034	ambiguous
REVEL	0.194	benign-leaning
SaProt	LLR -8.69	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.2	GERP -2.8, phastCons 1
Overall
CADD	23.9	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 0.0017% European (non-Finnish) · 20/1,179,856 alleles

Filtering AF 0.00111% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0009%

Overall 0.00144% 21/1,461,674 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0017%	58,993
Admixed American	0.00167%	60,010

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.Thr668Pro
Coding: c.2002A>C
MANE Select: NM_198060
dbSNP: rs1218484255
Type: single nucleotide variant
Location: chr10:113629626 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

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NRAP p.Asp633Tyr Uncertain significance ★★ ⚠ same condition
NRAP p.Gly277Val Uncertain significance ★★ ⚠ same condition
NRAP p.His1003Tyr Uncertain significance ★★ ⚠ same condition
NRAP p.His639Arg Uncertain significance ★★ ⚠ same condition
NRAP p.Lys1590Arg Uncertain significance ★★ ⚠ same condition
NRAP p.Lys794Gln 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/nrap-p-thr668pro (accessed [today's date]).

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