Is REN p.Ser133= (c.399G>T) pathogenic?

REN p.Ser133= (c.399G>T) is classified Uncertain significance in REN (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-29). Very rare (popmax 0.00935%, afr); Associated with renal tubular dysgenesis of genetic origin.

What condition is associated with REN p.Ser133= (c.399G>T)?

REN p.Ser133= (c.399G>T) is associated with renal tubular dysgenesis of genetic origin, familial juvenile hyperuricemic nephropathy type 2 (ClinVar).

How common is REN p.Ser133= (c.399G>T) in the general population?

REN p.Ser133= (c.399G>T) is very rare (popmax 0.00935%, afr) (gnomAD).

REN p.Ser133=

c.399G>T · VCV3578072

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00935%, afr)

Conditions

renal tubular dysgenesis of genetic origin

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.62	acceptor gain · deltas
Pangolin	Δ0.54	gain · loss 0.35 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP -3.7	GERP -3.6
Overall
CADD	14.06	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00935% African / African-American · 7/74,900 alleles

Filtering AF 0.00437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00309%

Overall 0.000434% 7/1,613,846 alleles · very rare

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: REN
Protein: p.Ser133=
Coding: c.399G>T
MANE Select: NM_001363642 · reported on NM_000537
Type: single nucleotide variant
Location: chr1:204160653 (GRCh38)
Structure: AlphaFold pLDDT 85.00

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

Disease context

renal tubular dysgenesis of genetic origin — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: familial juvenile hyperuricemic nephropathy type 2

Similar variants

REN p.Ser133Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
REN c.249+1G>A Pathogenic/Likely pathogenic ★★ same condition
REN p.Arg49Ter Pathogenic/Likely pathogenic ★★ same condition
REN p.Ala182Thr Uncertain significance ★★ ⚠ same condition
REN p.Arg119Cys Uncertain significance ★★ ⚠ same condition
REN p.Arg387Gln Uncertain significance ★★ ⚠ same condition
REN p.Arg395Trp Uncertain significance ★★ ⚠ same condition
REN p.Arg406Cys 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/ren-p-ser133 (accessed [today's date]).

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