Is RPAP1 p.Pro587Ser (c.1759C>T) pathogenic?

RPAP1 p.Pro587Ser (c.1759C>T) is classified Uncertain significance in RPAP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-13). AlphaMissense: likely benign (0.2811); Ultra-rare (popmax 0.0582%, sas).

How common is RPAP1 p.Pro587Ser (c.1759C>T) in the general population?

RPAP1 p.Pro587Ser (c.1759C>T) is ultra-rare (popmax 0.0582%, sas) (gnomAD).

What do computational predictors say about RPAP1 p.Pro587Ser (c.1759C>T)?

AlphaMissense predicts likely benign (score 0.2811) — an in-silico prediction, not a clinical call.

RPAP1 p.Pro587Ser

c.1759C>T · rs560065091 · VCV2601376

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2811 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0582%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2811	likely benign
REVEL	0.7	pathogenic-leaning
SaProt	LLR -8.37	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.6, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 16 kb · p 6.8e-05 · regional, not allelic
Overall
CADD	27.2	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 0.0582% South Asian · 53/91,076 alleles

Filtering AF 0.0457% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0412%

Overall 0.00335% 54/1,614,164 alleles · ultra-rare exomes 52/1,461,806 · genomes 2/152,358 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0582%	1,718
Middle Eastern	0.0165%	6,062

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: RPAP1
Protein: p.Pro587Ser
Coding: c.1759C>T
MANE Select: NM_015540
dbSNP: rs560065091
Type: single nucleotide variant
Location: chr15:41527056 (GRCh38)
Gene constraint: LOEUF 0.877 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.03

Full RPAP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

RPAP1 p.Ser3Leu Benign ★★ same type
RPAP1 p.Ala1022Val Uncertain significance ★ ⚠ same type
RPAP1 p.Ala1046Thr Uncertain significance ★ ⚠ same type
RPAP1 p.Ala1048Thr Uncertain significance ★ ⚠ same type
RPAP1 p.Ala1113Thr Uncertain significance ★ ⚠ same type
RPAP1 p.Ala1184Thr Uncertain significance ★ ⚠ same type
RPAP1 p.Ala1295Val Uncertain significance ★ ⚠ same type
RPAP1 p.Ala1310Val 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/rpap1-p-pro587ser (accessed [today's date]).

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