Is RAMP3 p.Pro87Ser (c.259C>T) pathogenic?

RAMP3 p.Pro87Ser (c.259C>T) is classified Uncertain significance in RAMP3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-04). AlphaMissense: likely benign (0.1452); Very rare (popmax 0.01%, amr).

How common is RAMP3 p.Pro87Ser (c.259C>T) in the general population?

RAMP3 p.Pro87Ser (c.259C>T) is very rare (popmax 0.01%, amr) (gnomAD).

What do computational predictors say about RAMP3 p.Pro87Ser (c.259C>T)?

AlphaMissense predicts likely benign (score 0.1452) — an in-silico prediction, not a clinical call.

RAMP3 p.Pro87Ser

c.259C>T · rs369095090 · VCV3151356

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1452 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.01%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1452	likely benign
REVEL	0.26	benign-leaning
SaProt	LLR -9.57	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.1	GERP 1, phastCons 0.99
Regional constraint	o/e 0.98	unconstrained · MANE · 26 kb · p 0.73 · regional, not allelic
Overall
CADD	20.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.01% Admixed American · 6/60,008 alleles

Filtering AF 0.00428% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00295%

Overall 0.000868% 14/1,613,698 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.01%	10,001
African / African-American	0.00134%	74,906
European (non-Finnish)	0.000593%	168,576

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: RAMP3
Protein: p.Pro87Ser
Coding: c.259C>T
MANE Select: NM_005856
dbSNP: rs369095090
Type: single nucleotide variant
Location: chr7:45183224 (GRCh38)
Gene constraint: LOEUF 1.712 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.97 · 7 PDB
Residue 87: a disulfide bond; an α-helix

Full RAMP3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

RAMP3 p.Arg7Trp Uncertain significance ★ ⚠ same type
RAMP3 p.Asp107Tyr Uncertain significance ★ ⚠ same type
RAMP3 p.Cys22Arg Uncertain significance ★ ⚠ same type
RAMP3 p.Glu30Asp Uncertain significance ★ ⚠ same type
RAMP3 p.Gly135Val Uncertain significance ★ ⚠ same type
RAMP3 p.Gly49Asp Uncertain significance ★ ⚠ same type
RAMP3 p.His110Tyr Uncertain significance ★ ⚠ same type
RAMP3 p.Leu11Phe 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/ramp3-p-pro87ser (accessed [today's date]).

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