Is RRM1 p.Val583Phe (c.1747G>T) pathogenic?

RRM1 p.Val583Phe (c.1747G>T) is classified Uncertain significance in RRM1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-15). AlphaMissense: likely benign (0.1032); Very rare (popmax 0.00162%, nfe).

How common is RRM1 p.Val583Phe (c.1747G>T) in the general population?

RRM1 p.Val583Phe (c.1747G>T) is very rare (popmax 0.00162%, nfe) (gnomAD).

What do computational predictors say about RRM1 p.Val583Phe (c.1747G>T)?

AlphaMissense predicts likely benign (score 0.1032) — an in-silico prediction, not a clinical call.

RRM1 p.Val583Phe

c.1747G>T · rs201133430 · VCV2237778

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1032 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00162%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1032	likely benign
REVEL	0.035	moderately benign-leaning
SaProt	LLR -10.02	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>A here scores Δ0.25 · evaluated, not missing
Constraint at this position
Conservation	phyloP -0.052	GERP -1.8
Regional constraint	o/e 0.77	unconstrained · MANE · 5,493 bp · p 0.0063 · regional, not allelic
Overall
CADD	18.95	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00162% European (non-Finnish) · 19/1,173,638 alleles

Filtering AF 0.00103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000834%

Overall 0.00118% 19/1,605,050 alleles · very rare exomes 17/1,453,092 · genomes 2/151,958 · 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: RRM1
Protein: p.Val583Phe
Coding: c.1747G>T
MANE Select: NM_001033
dbSNP: rs201133430
Type: single nucleotide variant
Location: chr11:4129128 (GRCh38)
Gene constraint: LOEUF 0.242 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 92.43 · 12 PDB
Residue 583: an α-helix

Full RRM1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

RRM1 p.Arg381His Likely pathogenic ★★ ⚠ same type
RRM1 p.Leu121= Benign ★★ same type
RRM1 p.Ala467Ser Uncertain significance ★ ⚠ same type
RRM1 p.Ala511Thr Uncertain significance ★ ⚠ same type
RRM1 p.Ala522Ser Uncertain significance ★ ⚠ same type
RRM1 p.Ala547Gly Uncertain significance ★ same type
RRM1 p.Arg130Cys Uncertain significance ★ ⚠ same type
RRM1 p.Arg212His 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/rrm1-p-val583phe (accessed [today's date]).

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