Is RFC4 p.Leu289Arg (c.866T>G) pathogenic?

RFC4 p.Leu289Arg (c.866T>G) is classified Conflicting classifications of pathogenicity in RFC4 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2026-02-07). AlphaMissense: likely pathogenic (0.8788); Very rare (popmax 8.48e-05%, nfe); Associated with Morimoto-Ryu-Malicdan neuromuscular syndrome.

What condition is associated with RFC4 p.Leu289Arg (c.866T>G)?

RFC4 p.Leu289Arg (c.866T>G) is associated with Morimoto-Ryu-Malicdan neuromuscular syndrome (ClinVar).

How common is RFC4 p.Leu289Arg (c.866T>G) in the general population?

RFC4 p.Leu289Arg (c.866T>G) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about RFC4 p.Leu289Arg (c.866T>G)?

AlphaMissense predicts likely pathogenic (score 0.8788) — an in-silico prediction, not a clinical call.

RFC4 p.Leu289Arg

c.866T>G · VCV4532813

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8788 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Morimoto-Ryu-Malicdan neuromuscular syndrome

⚠ Built without this gene's context — gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up for this page. why

Computational evidence

Protein change
AlphaMissense	0.8788	likely pathogenic
REVEL	0.753	pathogenic-leaning
SaProt	LLR -14.42	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 11	GERP 1.7, phastCons 1
Regional constraint	o/e 1.61	unconstrained · MANE · 2,554 bp · p 8.7e-16 · regional, not allelic
Overall
CADD	25.6	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 8.48e-05% European (non-Finnish) · 1/1,179,658 alleles

Overall 6.2e-05% 1/1,613,698 alleles · very rare exomes 1/1,461,464 · genomes 0/152,234 · 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: RFC4
Protein: p.Leu289Arg
Coding: c.866T>G
MANE Select: NM_002916
Type: single nucleotide variant
Location: chr3:186790342 (GRCh38)

Full RFC4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Morimoto-Ryu-Malicdan neuromuscular syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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/rfc4-p-leu289arg (accessed [today's date]).

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