Is REN p.Arg396Cys (c.1186C>T) pathogenic?

REN p.Arg396Cys (c.1186C>T) is classified Uncertain significance in REN (ClinVar, Single submitter, 1 submitter). AlphaMissense: likely benign (0.1868); Very rare (popmax 0.00439%, sas); Associated with familial juvenile hyperuricemic nephropathy type 2.

What condition is associated with REN p.Arg396Cys (c.1186C>T)?

REN p.Arg396Cys (c.1186C>T) is associated with familial juvenile hyperuricemic nephropathy type 2 (ClinVar).

How common is REN p.Arg396Cys (c.1186C>T) in the general population?

REN p.Arg396Cys (c.1186C>T) is very rare (popmax 0.00439%, sas) (gnomAD).

What do computational predictors say about REN p.Arg396Cys (c.1186C>T)?

AlphaMissense predicts likely benign (score 0.1868) — an in-silico prediction, not a clinical call.

REN p.Arg396Cys

c.1186C>T · rs763037834 · VCV1339184

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1868 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00439%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

familial juvenile hyperuricemic nephropathy type 2

Computational evidence

Protein change
AlphaMissense	0.1868	likely benign
REVEL	0.224	benign-leaning
SaProt	LLR -9.23	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP -2.6, phastCons 1
Overall
CADD	23.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00439% South Asian · 4/91,094 alleles

Filtering AF 0.00143% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.000558% 9/1,614,088 alleles · very rare exomes 8/1,461,832 · genomes 1/152,256 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00439%	22,773
Admixed American	0.00167%	60,018
African / African-American	0.00133%	74,946
European (non-Finnish)	0.000254%	393,351

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.Arg396Cys
Coding: c.1186C>T
MANE Select: NM_000537
dbSNP: rs763037834
Type: single nucleotide variant
Location: chr1:204155051 (GRCh38)
Structure: AlphaFold pLDDT 85.00

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

Disease context

familial juvenile hyperuricemic nephropathy type 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

REN p.Arg396His 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-arg396cys (accessed [today's date]).

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