Is REN p.Ser108Ala (c.322T>G) pathogenic?

REN p.Ser108Ala (c.322T>G) is classified Conflicting classifications of pathogenicity in REN (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-04-25). AlphaMissense: likely benign (0.0733); Ultra-rare (popmax 0.0858%, sas); Associated with renal tubular dysgenesis of genetic origin.

What condition is associated with REN p.Ser108Ala (c.322T>G)?

REN p.Ser108Ala (c.322T>G) is associated with renal tubular dysgenesis of genetic origin, familial juvenile hyperuricemic nephropathy type 2 (ClinVar).

How common is REN p.Ser108Ala (c.322T>G) in the general population?

REN p.Ser108Ala (c.322T>G) is ultra-rare (popmax 0.0858%, sas) (gnomAD).

What do computational predictors say about REN p.Ser108Ala (c.322T>G)?

AlphaMissense predicts likely benign (score 0.0733) — an in-silico prediction, not a clinical call.

REN p.Ser108Ala

c.322T>G · rs556759055 · VCV2358379

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0733 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0858%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

renal tubular dysgenesis of genetic origin

Computational evidence

Protein change
AlphaMissense	0.0733	likely benign
REVEL	0.129	moderately benign-leaning
SaProt	LLR -8.13	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.20	donor loss, 6 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 2.3	GERP -1.1, phastCons 0.98
Overall
CADD	9.314	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 0.0858% South Asian · 77/89,722 alleles

Filtering AF 0.0704% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0646%

Overall 0.00528% 85/1,609,314 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0858%	1,165
Remaining individualsnot grpmax-eligible	0.0112%	8,900
African / African-American	0.00133%	74,946

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.Ser108Ala
Coding: c.322T>G
MANE Select: NM_001363642 · reported on NM_000537
dbSNP: rs556759055
Type: single nucleotide variant
Location: chr1:204161343 (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 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
REN p.Arg43Gln 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-ser108ala (accessed [today's date]).

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