Is NRAP p.Pro977Ser (c.2929C>T) pathogenic?

NRAP p.Pro977Ser (c.2929C>T) is classified Uncertain significance in NRAP (ClinVar, Single submitter, 2 submitters; last evaluated 2025-04-09). AlphaMissense: likely pathogenic (0.824); Rare (popmax 0.513%, afr); Associated with Cardiovascular phenotype.

What condition is associated with NRAP p.Pro977Ser (c.2929C>T)?

NRAP p.Pro977Ser (c.2929C>T) is associated with Cardiovascular phenotype (ClinVar).

How common is NRAP p.Pro977Ser (c.2929C>T) in the general population?

NRAP p.Pro977Ser (c.2929C>T) is rare (popmax 0.513%, afr) (gnomAD).

What do computational predictors say about NRAP p.Pro977Ser (c.2929C>T)?

AlphaMissense predicts likely pathogenic (score 0.824) — an in-silico prediction, not a clinical call.

NRAP p.Pro977Ser

c.2929C>T · rs115942015 · VCV3045820

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.824 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.513%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.824	likely pathogenic · top 6% in NRAP
REVEL	0.456	indeterminate
SaProt	LLR -10.96	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.8, phastCons 1
Overall
CADD	24.8	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 0.513% African / African-American · 385/74,986 alleles

Filtering AF 0.471% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.455%

Overall 0.0263% 424/1,612,574 alleles · rare exomes 197/1,460,376 · genomes 227/152,198 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.513%	195
Admixed American	0.035%	2,858
Remaining individualsnot grpmax-eligible	0.0224%	4,459
European (non-Finnish)	0.000339%	294,670

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.Pro977Ser
Coding: c.2929C>T
MANE Select: NM_198060
dbSNP: rs115942015
Type: single nucleotide variant
Location: chr10:113617499 (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

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

NRAP p.Pro977Leu Uncertain significance ★★ same residue
NRAP p.Pro977Arg Uncertain significance ★ ⚠ same residue
NRAP p.Ala29Gly Uncertain significance ★★ ⚠ same condition
NRAP p.Arg1330Gln Uncertain significance ★★ ⚠ same condition
NRAP p.Arg428Cys Uncertain significance ★★ ⚠ same condition
NRAP p.Asn1233Lys Uncertain significance ★★ ⚠ same condition
NRAP p.Gly748Arg Uncertain significance ★★ ⚠ same condition
NRAP p.Pro769Leu 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-pro977ser (accessed [today's date]).

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