Is REN p.Glu189Lys (c.565G>A) pathogenic?

REN p.Glu189Lys (c.565G>A) is classified Conflicting classifications of pathogenicity in REN (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-10-05). AlphaMissense: likely benign (0.0753); Ultra-rare (popmax 0.0102%, nfe); Associated with Inborn genetic diseases.

What condition is associated with REN p.Glu189Lys (c.565G>A)?

REN p.Glu189Lys (c.565G>A) is associated with Inborn genetic diseases (ClinVar).

How common is REN p.Glu189Lys (c.565G>A) in the general population?

REN p.Glu189Lys (c.565G>A) is ultra-rare (popmax 0.0102%, nfe) (gnomAD).

What do computational predictors say about REN p.Glu189Lys (c.565G>A)?

AlphaMissense predicts likely benign (score 0.0753) — an in-silico prediction, not a clinical call.

REN p.Glu189Lys

c.565G>A · rs771032027 · VCV2717933

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0753 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0102%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0753	likely benign
REVEL	0.135	moderately benign-leaning
SaProt	LLR -2.91	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 1.9	GERP -1.2, phastCons 1
Overall
CADD	15.92	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 0.0102% European (non-Finnish) · 120/1,180,040 alleles

Filtering AF 0.00867% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00812%

Overall 0.00805% 130/1,614,062 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0102%	9,834
Admixed American	0.00667%	14,999
Remaining individualsnot grpmax-eligible	0.0048%	20,829
African / African-American	0.004%	24,974

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.Glu189Lys
Coding: c.565G>A
MANE Select: NM_001363642 · reported on NM_000537
dbSNP: rs771032027
Type: single nucleotide variant
Location: chr1:204159523 (GRCh38)
Structure: AlphaFold pLDDT 85.00

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

KCTD11 p.Glu189Asp Uncertain significance ★ ⚠ same residue
REN p.Lys139Ter Pathogenic ★★ same condition
REN p.Arg119His Uncertain significance ★★ ⚠ same condition
REN p.Arg399His Uncertain significance ★★ ⚠ same condition
REN p.Gln160Arg Uncertain significance ★★ ⚠ same condition
REN p.Glu253Lys Uncertain significance ★★ ⚠ same condition
REN p.Glu310Lys Uncertain significance ★★ ⚠ same condition
REN p.Glu89Lys 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-glu189lys (accessed [today's date]).

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