Is RFX5 p.Ser439fs (c.1317_1320del) pathogenic?

RFX5 p.Ser439fs (c.13171320del) is classified Likely pathogenic in RFX5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-04). Very rare (popmax 0.0011%, sas).

How common is RFX5 p.Ser439fs (c.1317_1320del) in the general population?

RFX5 p.Ser439fs (c.1317_1320del) is very rare (popmax 0.0011%, sas) (gnomAD).

RFX5 p.Ser439fs

c.1317_1320del · VCV3765395

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

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 1.6	GERP 0.66, phastCons 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,088 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000274% 4/1,461,890 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,088
European (non-Finnish)	0.000254%	393,348

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: RFX5
Protein: p.Ser439fs
Coding: c.1317_1320del
MANE Select: NM_001025603
Type: Microsatellite
Location: chr1:151342717 (GRCh38)
Gene constraint: LOEUF 0.884 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 58.48 · 3 PDB
Residue 439: a UniProt-annotated variant site (in mhc2d3; likely pathogenic); the 'disordered' region

Full RFX5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

RFX5 p.Ser439Ile Uncertain significance ★ ⚠ same residue
RFX5 p.Leu124fs Pathogenic ★ same type
RFX5 p.Asp115del Uncertain significance ★ same type
RFX5 p.Asn414fs 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/rfx5-p-ser439fs (accessed [today's date]).

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