Is RPAP1 p.Phe261Val (c.781T>G) pathogenic?

RPAP1 p.Phe261Val (c.781T>G) is classified Uncertain significance in RPAP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-12). AlphaMissense: ambiguous (0.4629); Very rare (popmax 0.0022%, sas).

How common is RPAP1 p.Phe261Val (c.781T>G) in the general population?

RPAP1 p.Phe261Val (c.781T>G) is very rare (popmax 0.0022%, sas) (gnomAD).

What do computational predictors say about RPAP1 p.Phe261Val (c.781T>G)?

AlphaMissense predicts ambiguous (score 0.4629) — an in-silico prediction, not a clinical call.

RPAP1 p.Phe261Val

c.781T>G · VCV3947346

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4629 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Computational evidence

Protein change
AlphaMissense	0.4629	ambiguous
REVEL	0.369	indeterminate
SaProt	LLR -11.37	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.4, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 16 kb · p 6.8e-05 · regional, not allelic
Overall
CADD	26.3	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 0.0022% South Asian · 2/91,012 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000186% 3/1,611,860 alleles · very rare exomes 3/1,459,734 · genomes 0/152,126 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,506
Remaining individualsnot grpmax-eligible	0.0016%	62,392

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.Phe261Val
Coding: c.781T>G
MANE Select: NM_015540
Type: single nucleotide variant
Location: chr15:41531185 (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-phe261val (accessed [today's date]).

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