Is RO60 p.Ser302Pro (c.904T>C) pathogenic?

RO60 p.Ser302Pro (c.904T>C) is classified Uncertain significance in RO60 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-10). AlphaMissense: likely benign (0.1249); Very rare (popmax 0.00382%, nfe).

How common is RO60 p.Ser302Pro (c.904T>C) in the general population?

RO60 p.Ser302Pro (c.904T>C) is very rare (popmax 0.00382%, nfe) (gnomAD).

What do computational predictors say about RO60 p.Ser302Pro (c.904T>C)?

AlphaMissense predicts likely benign (score 0.1249) — an in-silico prediction, not a clinical call.

RO60 p.Ser302Pro

c.904T>C · VCV4155961

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1249 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00382%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1249	likely benign
REVEL	0.112	moderately benign-leaning
SaProt	LLR -9.36	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.94	GERP 0.88, phastCons 0.99
Regional constraint	o/e 0.86	unconstrained · MANE · 16 kb · p 0.00049 · regional, not allelic
Overall
CADD	19.63	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 0.00382% European (non-Finnish) · 45/1,178,402 alleles

Filtering AF 0.00291% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0026%

Overall 0.0028% 45/1,609,666 alleles · very rare exomes 43/1,457,496 · genomes 2/152,170 · 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: RO60
Protein: p.Ser302Pro
Coding: c.904T>C
MANE Select: NM_001173524
Type: single nucleotide variant
Location: chr1:193076603 (GRCh38)
Gene constraint: LOEUF 0.519 · pLI 0.95 (gnomAD)
Structure: AlphaFold pLDDT 93.42 · 1 PDB
Residue 302: the trove domain

Full RO60 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

RO60 p.Ser302Tyr Uncertain significance ★ ⚠ same residue
RO60 p.Lys270= Benign ★★ same type
RO60 p.Ala153Val Uncertain significance ★ ⚠ same type
RO60 p.Ala165Ser Uncertain significance ★ ⚠ same type
RO60 p.Ala317Asp Uncertain significance ★ same type
RO60 p.Ala461Thr Uncertain significance ★ ⚠ same type
RO60 p.Ala461Val Uncertain significance ★ ⚠ same type
RO60 p.Ala480Val 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/ro60-p-ser302pro (accessed [today's date]).

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