Is RIPPLY2 p.Pro52Arg (c.155C>G) pathogenic?

RIPPLY2 p.Pro52Arg (c.155C>G) is classified Uncertain significance in RIPPLY2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-29). AlphaMissense: likely benign (0.0648); Ultra-rare (popmax 0.0165%, sas).

How common is RIPPLY2 p.Pro52Arg (c.155C>G) in the general population?

RIPPLY2 p.Pro52Arg (c.155C>G) is ultra-rare (popmax 0.0165%, sas) (gnomAD).

What do computational predictors say about RIPPLY2 p.Pro52Arg (c.155C>G)?

AlphaMissense predicts likely benign (score 0.0648) — an in-silico prediction, not a clinical call.

RIPPLY2 p.Pro52Arg

c.155C>G · rs775895308 · VCV3154705

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0648 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0648	likely benign
REVEL	0.011	strongly benign-leaning
SaProt	LLR -5.63	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 -0.66	GERP -4.2
Regional constraint	o/e 1.25	unconstrained · MANE · 3,969 bp · p 0.00092 · regional, not allelic
Overall
CADD	6.613	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 0.0165% South Asian · 15/90,958 alleles

Filtering AF 0.0101% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00812%

Overall 0.00093% 15/1,613,130 alleles · ultra-rare exomes 15/1,460,788 · genomes 0/152,342 · joint denominator

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: RIPPLY2
Protein: p.Pro52Arg
Coding: c.155C>G
MANE Select: NM_001009994
dbSNP: rs775895308
Type: single nucleotide variant
Location: chr6:83853754 (GRCh38)
Gene constraint: LOEUF 1.76 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.67
Residue 52: the 'disordered' region

Full RIPPLY2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

RIPPLY2 p.Ala14Ser Uncertain significance ★★ ⚠ same type
RIPPLY2 p.Ala14Thr Uncertain significance ★★ ⚠ same type
RIPPLY2 p.Ala34Thr Uncertain significance ★★ ⚠ same type
RIPPLY2 p.Glu118Lys Uncertain significance ★★ ⚠ same type
RIPPLY2 p.Gly9Cys Uncertain significance ★★ ⚠ same type
RIPPLY2 p.Met59Thr Uncertain significance ★★ ⚠ same type
RIPPLY2 c.175-19C>T Likely benign ★★ same type
RIPPLY2 p.Ala4= Benign ★★ 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/ripply2-p-pro52arg (accessed [today's date]).

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