Is NRAP p.Phe1069Leu (c.3207T>A) pathogenic?

NRAP p.Phe1069Leu (c.3207T>A) is classified Conflicting classifications of pathogenicity in NRAP (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-04-09). AlphaMissense: likely pathogenic (0.9266); Rare (popmax 0.949%, afr); Associated with Cardiovascular phenotype.

What condition is associated with NRAP p.Phe1069Leu (c.3207T>A)?

NRAP p.Phe1069Leu (c.3207T>A) is associated with Cardiovascular phenotype (ClinVar).

How common is NRAP p.Phe1069Leu (c.3207T>A) in the general population?

NRAP p.Phe1069Leu (c.3207T>A) is rare (popmax 0.949%, afr) (gnomAD).

What do computational predictors say about NRAP p.Phe1069Leu (c.3207T>A)?

AlphaMissense predicts likely pathogenic (score 0.9266) — an in-silico prediction, not a clinical call.

NRAP p.Phe1069Leu

c.3207T>A · rs115445984 · VCV3037480

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9266 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.949%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.9266	likely pathogenic · top 2% in NRAP
REVEL	0.378	indeterminate
SaProt	LLR -9.31	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.2	GERP 1.6, phastCons 1
Overall
CADD	23.7	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 0.949% African / African-American · 712/75,014 alleles

Filtering AF 0.891% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.868%

Overall 0.0507% 818/1,612,966 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.949%	105
Admixed American	0.0716%	1,396
Remaining individualsnot grpmax-eligible	0.0656%	1,524
South Asian	0.00439%	22,764
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,598
European (non-Finnish)	0.00144%	69,348

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.Phe1069Leu
Coding: c.3207T>A
MANE Select: NM_198060
dbSNP: rs115445984
Type: single nucleotide variant
Location: chr10:113614276 (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.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
NRAP p.Ser169Arg Uncertain significance ★★ ⚠ same condition
NRAP p.Thr903Met 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-phe1069leu (accessed [today's date]).

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