Is RFC4 p.Val355fs (c.1064_1065del) pathogenic?

RFC4 p.Val355fs (c.10641065del) is classified Pathogenic in RFC4 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-11-13). Very rare (popmax 0.0055%, sas); Associated with Morimoto-Ryu-Malicdan neuromuscular syndrome.

What condition is associated with RFC4 p.Val355fs (c.1064_1065del)?

RFC4 p.Val355fs (c.1064_1065del) is associated with Morimoto-Ryu-Malicdan neuromuscular syndrome (ClinVar).

How common is RFC4 p.Val355fs (c.1064_1065del) in the general population?

RFC4 p.Val355fs (c.1064_1065del) is very rare (popmax 0.0055%, sas) (gnomAD).

RFC4 p.Val355fs

c.1064_1065del · VCV3376525

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.0055%, sas)

Conditions

Morimoto-Ryu-Malicdan neuromuscular syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (11 of 11) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.8	GERP 1.8, phastCons 1
Overall
CADD	29.5	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0055% South Asian · 5/90,986 alleles

Filtering AF 0.00211% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00137%

Overall 0.000993% 16/1,610,944 alleles · very rare exomes 15/1,458,654 · genomes 1/152,290 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0055%	18,197
European (non-Finnish)	0.000934%	107,020

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.Val355fs
Coding: c.1064_1065del
MANE Select: NM_002916
Type: Microsatellite
Location: chr3:186789996 (GRCh38)
Gene constraint: LOEUF 1.096 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.68 · 16 PDB
Residue 355: an α-helix

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

Similar variants

RFC4 p.Ala303del Pathogenic same condition
RFC4 c.290+5G>T Likely pathogenic ★ same condition
RFC4 c.996+4dup Likely pathogenic ★ same condition
RFC4 p.Asp275del Likely pathogenic ★ same condition
RFC4 p.Met356fs Likely pathogenic ★ same condition
RFC4 p.Cys281Arg Uncertain significance ★ ⚠ same condition
RFC4 p.Glu344Lys Conflicting classifications of pathogenicity ★ ⚠ same condition
RFC4 p.Ile327del Uncertain significance ★ same condition

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-val355fs (accessed [today's date]).

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