Is RIPPLY2 p.Pro84Ser (c.250C>T) pathogenic?

RIPPLY2 p.Pro84Ser (c.250C>T) is classified Uncertain significance in RIPPLY2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-24). AlphaMissense: likely pathogenic (0.9652); No allele count reported in gnomAD v4.1 (AN 1,498,514).

How common is RIPPLY2 p.Pro84Ser (c.250C>T) in the general population?

RIPPLY2 p.Pro84Ser (c.250C>T) is no allele count reported in gnomAD v4.1 (AN 1,498,514) (gnomAD).

What do computational predictors say about RIPPLY2 p.Pro84Ser (c.250C>T)?

AlphaMissense predicts likely pathogenic (score 0.9652) — an in-silico prediction, not a clinical call.

RIPPLY2 p.Pro84Ser

c.250C>T · VCV4731692

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9652 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,498,514)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.9652	likely pathogenic · top 5% in RIPPLY2
REVEL	0.516	indeterminate
SaProt	LLR -13.43	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.4	GERP 2.7, phastCons 1
Regional constraint	o/e 1.25	unconstrained · MANE · 3,969 bp · p 0.00092 · regional, not allelic
Overall
CADD	26.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

No allele count reported in gnomAD v4.1 (AN 1,498,514). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: RIPPLY2
Protein: p.Pro84Ser
Coding: c.250C>T
MANE Select: NM_001009994
Type: single nucleotide variant
Location: chr6:83857252 (GRCh38)
Gene constraint: LOEUF 1.76 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.67
Residue 84: the 'ripply homology domain' region; a UniProt-annotated variant site (in scdo6; likely pathogenic)

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

Similar variants

RIPPLY2 p.Pro84Leu Uncertain significance ★ ⚠ same residue
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

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-pro84ser (accessed [today's date]).

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