Is RRM2B p.Ser181Pro (c.541T>C) pathogenic?

RRM2B p.Ser181Pro (c.541T>C) is classified Uncertain significance in RRM2B (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-28). AlphaMissense: likely pathogenic (0.8094); Absent from gnomAD v4.1.

How common is RRM2B p.Ser181Pro (c.541T>C) in the general population?

RRM2B p.Ser181Pro (c.541T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about RRM2B p.Ser181Pro (c.541T>C)?

AlphaMissense predicts likely pathogenic (score 0.8094) — an in-silico prediction, not a clinical call.

RRM2B p.Ser181Pro

c.541T>C · rs2488859550 · VCV1962264

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8094 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8094	likely pathogenic
REVEL	0.743	pathogenic-leaning
SaProt	LLR -10.99	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8	GERP 0.5, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 19 kb · p 0.00015 · regional, not allelic
Overall
CADD	23.4	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: RRM2B
Protein: p.Ser181Pro
Coding: c.541T>C
MANE Select: NM_015713
dbSNP: rs2488859550
Type: single nucleotide variant
Location: chr8:102224055 (GRCh38)
Gene constraint: LOEUF 0.688 · pLI 0.27 (gnomAD)
Structure: AlphaFold pLDDT 85.73 · 3 PDB
Residue 181: a β-strand

Full RRM2B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

RRM2B c.322-2A>G Pathogenic ★★ same type
RRM2B c.455+1G>A Likely pathogenic ★★ same type
RRM2B p.Arg110Cys Likely pathogenic ★★ same type
RRM2B p.Arg174Ter Pathogenic/Likely pathogenic ★★ same type
RRM2B p.Arg327Ter Pathogenic ★★ same type
RRM2B p.Arg41Trp Pathogenic/Likely pathogenic ★★ same type
RRM2B p.Gly229Val Pathogenic/Likely pathogenic ★★ same type
RRM2B p.Ile224Ser Pathogenic/Likely pathogenic ★★ 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/rrm2b-p-ser181pro (accessed [today's date]).

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